KR100323167B1 - Aralkyl and aralkylidene heterocyclic lactams and imides - Google Patents

Abstract

The present invention relates to compounds of formula (I), intermediates useful for their preparation, pharmaceutical compositions containing them and their medical uses:

Formula I

Where

R ¹ is a group of the group G ¹ , G ² , G ³ , G ⁴ or G ^{5 shown below} ;

Y is an optionally substituted (C ₁ -C ₄ ) heteroalkyl bridge which, together with the atoms to which it is attached, forms a 5-7 membered heterocycle containing _2-4 heteroatoms.

This compound is useful as a psychotherapeutic agent.

Description

Aralkyl and aralkylidene heterocyclic lactams and imides

European Patent Publication No. 434,561, published June 26, 1991, mentions 7-alkyl, alkoxy and hydroxy substituted-1- (4-substituted-1-piperazinyl) -naphthalene. This compound is referred to as 5-HT ₁ antagonist and agent useful in the treatment of migraine, depression, anxiety, schizophrenia, stress and pain.

European Patent Publication No. 343,050, published November 23, 1989, discloses 7-unsubstituted, halogenated, methoxy substituted-1- (4-substituted-1-piperazinyl useful as 5-HT _1A ligand therapeutics. )-Naphthalene is mentioned.

PCT Publication No. WO 94/21619, published September 29, 1994, mentions naphthalene derivatives as 5-HT ₁ agonists and antagonists.

PCT Publication No. WO 96/00720, published January 11, 1996, mentions naphthyl ethers useful as 5-HT ₁ agonists and antagonists.

European Patent Publication No. 701,819, published March 20, 1996, mentions the use of 5-HT ₁ agonists and antagonists used with 5-HT reuptake inhibitors.

Glennon et al., Et al., "5-HT _1D Serotonin Receptors", Clinical Drug Res. Dev. , 22 , 25-36 (1991), refer to 7-methoxy-1- (1-piperazinyl) -naphthalene useful as 5-HT ₁ ligand.

Glenon has been described in his literature "Serotonin Receptors: Clinical Implications", Neuroscience and Behavioral Reviews , 14 , 35-47 (1990) as pharmacological effects associated with serotonin receptors, appetite suppression, temperature regulation, cardiovascular / hypertensive effects, sleep, Psychosis, anxiety, depression, nausea, vomiting, Alzheimer's disease, Parkinson's disease and Huntington's disease.

International Patent Application WO 95/31988, published November 30, 1995, discloses depression, systemic anxiety, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, memory disorder, anorexia nervosa, anorexia nervosa , Central nervous system (CNS) disorders such as Parkinson's disease, delayed dyskinesia, endocrine disorders such as hyperprolactinemia, vasospasm (particularly cerebral vessels) and gastrointestinal disorders associated with hypertension, movement and secretion changes, and sexual dysfunction To treat 5-HT _1A antagonists with 5-HT _1D antagonists.

Maura, G. (Maura, G) including the literature [J.Neurochem, 66 (1), pp 203-209 (1996)] is a selective 5-HT _1A receptors or 5-HT _1D receptors and both the 5-HT _1A receptors The administration of selective antagonists in the study suggests that therapies can lead to significant improvements in the treatment of multifaceted syndrome, human cerebellar ataxia, for which no treatment has been established.

European Patent Publication No. 666,261, published August 9, 1995, claims thiazine and thiomorpholine derivatives as useful in the treatment of cataracts.

Summary of the Invention

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Where

R ¹ is a group of the group G ¹ , G ² , G ³ , G ⁴ , G ⁵ , G ⁶ or G ^{7 shown below} ;

a is 0 to 8;

R ¹³ are each independently selected from G ¹ of the piperazine ring, or G ² of the piperidine from one of the ring carbons of the ring, the available binding sites of G ¹ of the piperazine ring, or G ² of the piperidine or like Dean ring having in addition to another ring carbon or a ring nitrogen (C ₁ -C ₄₎ alkyl or (C ₁ -C ₄₎ methylene bridge, or, to a ring carbon of R ⁶ having an available bonding sites (C ₁ -C ₄₎ alkyl Or a (C ₁ -C ₄ ) methylene bridge;

E is oxygen, sulfur, SO or SO ₂ ;

X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C ₁ -C ₆ ) alkyl, hydroxy, trifluoromethyl, (C ₁ -C ₆ ) alkoxy, -SO _t (C ₁ -C ₆ ) alkyl, where t is 0, 1 or 2, -CO ₂ R ¹⁰ or -CONR ¹¹ R ¹² ;

Y is 1,3-oxazolidin-4-one-5-yl, 1,3-oxazolidin-2,4-dione-5-yl, 4,5-dihydro-1 with the atoms to which it is attached , 2-oxazolidin-3-one-4-yl, 1,3-thiazolidin-4-one-5-yl, 1,3-thiazolidin-2,4-dione-5-yl, 1 , 3-pyrazolidin-4-one-5-yl, 1,3-imidazolidine-2,4-dione-5-yl, 1,2-pyrazolidin-3-one-4-yl, 1,2-thiazolidine-1,1,3-trion-4-yl, 1,2-thiazolidin-3-one-4-yl, tetrahydro-1,2-oxazin-3-one -4-yl, tetrahydro-1,3-oxazin-4-one-5-yl, tetrahydro-1,3-oxazine-2,4-dione-5-yl, morpholin-3-one- 2-yl, morpholine-3,5-dione-2-yl, 2,3-dihydro-1,4-oxazin-3-one-2-yl, tetrahydro-1,3-thiazine-4 -One-5-yl, tetrahydro-1,3-thiazine-2,4-dione-5-yl, tetrahydro-1,2-thiazin-3-one-4-yl, thiomorpho-3 -On-2-yl, thiomorpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-thiazin-3-one-2-yl, hexahydro-1,2- Diazin-3-one-4-yl, 4,5-dihydro-2H -Pyridazin-3-one-4-yl, hexahydro-1,3-diazin-4-one-5-yl, hexahydro-1,3-diazine-2,4-dione-5-yl, Piperazin-2-one-3-yl, piperazine-2,6-dione-3-yl, tetrahydro-1,3,4-thiadiazin-5-one-6-yl, 5,6-di Hydro-1,3,4-thiadiazine-5-one-6-yl, 1,3,4-oxadiazine-5-one-6-yl, 5,6-dihydro-1,2,4 Oxadiazine-5-one-6 days, tetrahydro-1,2,4-oxadiazine-5-one-6-day, 1,2,4-triazine-5-one-6-day, Tetrahydro-1,2,4-oxadiazine-5-one-6-yl, 5,6-dihydro-1,2,4-oxadiazine-5-one-6-yl, 1,2, 4-oxadiazine-3,5-dione-6-yl, 1,2,4-trazin-6-one-5-yl, hexahydro-1,2-oxazin-3-one-2-yl , Hexahydro-1,3-oxazepin-4-one-5-yl, hexahydro-1,4-oxazepin-3-one-2-yl, hexahydro-1,4-oxazepine-3,5 -Dione-2-yl, hexahydro-1,4-oxazepine-3,5-dione-6-yl, 2,3,5,6-tetrahydro-1,4-oxazepine-5,7-dione -6-yl, hexahydro-1,4-jade Zepin-5-one-6-yl, hexahydro-1,3-oxazepine-2,4-dione-5-yl, hexahydro-1,2-thiazepin-3-on-4-yl, hexahydro -1,4-thiazepin-3-one-2-yl, 2,3,4,5-tetrahydro-1,4-thiazepin-3-one-2-yl, hexahydro-1,4-thia Zepin-3,5-dione-2-yl, hexahydro-1,4-thiazepin-3,5-dione-6-yl, 2,3,6,7-tetrahydro-1,4-thiazepine- 5-one-6-yl, 6,7-dihydro-1,4-thiazepin-5-one-6-yl, hexahydro-1,3-thiazepin-2,4-dione-5-yl, Hexahydro-1,2-diazepin-3-one-4-yl, hexahydro-1,3-diazepine-2,4-dione-5-yl, hexahydro-1,4-diazepin-2- On-3-yl, hexahydro-1,4-diazepin-5-one-6-yl, hexahydro-1,4-diazepine-5,7-dione-6-yl, hexahydro-1,3 , 5-thiadiazepin-3-one-7-yl, 4,5,6,7-tetrahydro-1,3,5-thiadiazepin-6-one-7-yl and 2,3,5, Selected from the group consisting of 6-tetrahydro-1,2,4-triazin-3,5-dione-7-yl 2 to 4 heteroatoms containing optionally to form a 5- to 7-membered heterocycle substituted to the (C ₁ -C ₄₎ heteroalkyl bridge (where the bond on any carbon atom which may have an additional bond, Substituents of the (C ₁ -C ₄ ) heteroalkyl bridge are chloro, fluoro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, trifluoromethyl or cyano and have further bonds bound to any nitrogen atom which may, (C ₁ -C ₄₎ heteroalkyl bridge substituents are (C ₁ -C ₆₎ alkyl is methyl or trifluoromethyl), and;

R ² is hydrogen, (C ₁ -C ₄ ) alkyl, phenyl or naphthyl, wherein phenyl or naphthyl is chloro, fluoro, bromo, iodo, (C ₁ -C ₆ ) alkyl, (C _1- C ₆₎ alkoxy, trifluoromethyl, cyano and -SO _k (C ₁ -C ₆₎ alkyl (wherein k is 0, may be optionally substituted with one or more substituents independently selected from 1 or 2) ;

R ³ is — (CH ₂ ) _m B, wherein m is 0, 1, 2 or 3 and B is hydrogen, phenyl, naphthyl or a 5 or 6 membered hetero containing 1 to 4 heteroatoms in the ring Aryl groups, wherein each of the phenyl, naphthyl and heteroaryl groups is chloro, fluoro, bromo, iodo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy- (C ₁ -C ₆ ) alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, -COOH and -SO _n (C ₁ -C ₆ ) alkyl, where n is 0, 1 Or 2) optionally substituted with one or more substituents independently selected from

R ⁶ is hydrogen, (C ₁ -C ₆ ) alkoxy or (C ₁ -C ₆ ) alkyl optionally substituted with one to three fluorine atoms, or [(C ₁ -C ₄ ) alkyl] aryl {where the aryl moiety is Phenyl, naphthyl or heteroaryl- (CH ₂ ) _q wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl, q is 0, 1, 2, 3 or 4), wherein the aryl and heteroaryl residues are chloro, fluoro, bromo, iodo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, tri fluoro, methyl, cyano and -SO _g (C ₁ -C ₆₎ alkyl may be optionally substituted with one or more substituents independently selected from (where g is 0, 1 or 2)}, and;

R ⁷ is hydrogen, (C ₁ -C ₆ ) alkyl, [(C ₁ -C ₄ ) alkyl] aryl {where the aryl moiety is phenyl, naphthyl or heteroaryl- (CH ₂ ) _r where the heteroaryl moiety is pyri Dill, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl, r is 0, 1, 2, 3 or 4), and the aryl and heteroaryl moieties Chloro, fluoro, bromo, iodo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, trifluoromethyl, C (= O)-(C ₁ -C ₆ ) alkyl, cya Optionally substituted with one or more substituents independently selected from no and —SO _j (C ₁ -C ₆ ) alkyl, wherein j is 0, 1 or 2;

Or R ⁶ and R ⁷ together form 2 to 4 carbon chains;

R ⁸ is hydrogen or (C ₁ -C ₃ ) alkyl;

R ⁹ is hydrogen or (C ₁ -C ₆ ) alkyl;

Or R ⁶ and R ⁹ together with the nitrogen atom to which they are attached form a 5-7 membered heteroalkyl ring which may contain 0-4 heteroatoms selected from nitrogen, sulfur and oxygen;

p is 1, 2 or 3;

R ¹⁰ , R ¹¹ and R ¹² are each independently selected from radicals as defined in the definition of R ² , or R ¹¹ and R ¹² together with 0 to 4 heteros selected from nitrogen, sulfur and oxygen with the nitrogen to which they are attached To form 5- to 7-membered heteroalkyl rings which may contain atoms;

The dashed line represents an optional double bond, where the dashed line in G ² is a double bond only if R ⁸ is absent.

More specific embodiments of the G ¹ and G ² groups are as follows:

The invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula (I). Acids used to prepare pharmaceutically acceptable acid addition salts of the aforementioned base compounds of the present invention may be hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate , Lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharide, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate non-toxic acid addition salts, ie, pharmaceutically acceptable anions, such as p-toluenesulfonate and pamoate [ie 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)] salts Acid to form a salt to contain.

The invention also relates to base addition salts of formula (I). Chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts of compounds of formula (I) which are inherently acidic are those capable of forming non-toxic base salts with compounds of formula (I). Such non-toxic base salts include those derived from pharmacologically acceptable cations such as alkali metal cations (eg potassium and sodium) and alkaline earth metal cations (eg calcium and magnesium), N-methylglucamine- (meglu) Water-soluble amine addition salts such as M) or other base salts of ammonium, lower alkanolammonium and pharmaceutically acceptable organic amines.

Compounds of the invention include not only all stereoisomers (eg cis and trans isomers) and optical isomers (eg R and S enantiomers) of the compounds of formula (I), but also racemates, diastereomers and other such isomers. Mixtures are included.

The compounds of the present invention may have olefinic double bonds. When such a bond is present, the compounds of the present invention exist as cis and trans structures and as mixtures of these structures.

Unless stated otherwise, the alkyl moieties of the alkyl and alkenyl groups mentioned herein as well as all other groups (eg alkoxy) mentioned herein may be straight or branched chains and may also be cyclic (eg cyclopropyl). , Cyclobutyl, cyclopentyl or cyclohexyl), linear or branched, and may contain cyclic moieties. Unless stated otherwise, halogens include fluorine, chlorine, bromine and iodine.

Preferred compounds of formula I include R ¹

Wherein R ⁶ is methyl and R ² is hydrogen.

Preferred compounds of formula (I) also include those wherein Y is 1,3-thiazolidine-2,4-dione-5-yl, 1,3-imidazolidine-2,4-dione-5- with the atoms to which it is attached Forming an optionally substituted 5- to 7-membered heterocycle selected from one, thiomorpholin-3-on-2-yl or morpholin-3-on-2-yl.

Preferred compounds of formula I also include those wherein R ³ is optionally substituted phenyl or-(CH ₂ ) -optionally substituted phenyl.

Specific examples of preferred compounds of formula (I) are as follows:

3- (4-Chlorophenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -imidazolidine-2,4-dione;

3- (4-chlorobenzyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -imidazolidine-2,4-dione;

3- (4-chlorobenzyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidine-2,4-dione;

4-benzyl-2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorobenzyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

3- (4-Chlorophenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidine-2,4-dione;

3- (4-Trifluoromethylphenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidine-2,4-dione;

2- [2- (4-methylpiperazin-1-yl) -benzylidene] -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one;

2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-Dichlorophenyl) -2- [2-fluoro-6- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -morpholin-3-one;

4- (3,4-Dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-Dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzyl] -thiomorpholin-3-one;

4-methyl-2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- (2-piperazin-1-ylbenzylidene) -thiomorpholin-3-one;

4-benzyl-2- [2- (4-methylpiperazin-1-yl) -benzylidene] -1,1-dioxothiomorpholin-3-one;

4- (3,4-Dichlorophenyl) -2- [3-fluoro-2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-Dichlorophenyl) -2- [5-fluoro-2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -5-trifluoromethylbenzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- {2- [4- (2-methoxyethyl) piperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (4-isopropylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (4-ethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (4-Chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

2- [2-Chloro-6- (4-methylpiperazin-1-yl) -benzylidene] -4- (3,4-dichlorophenyl) -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -4-trifluoromethylbenzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -1-oxo-thiomorpholin-3-one;

4- (3,4-Dichlorophenyl) -2- (5-fluoro-2-piperazin-1-yl-benzylidene) -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [3,6-difluoro-2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-Dichlorophenyl) -2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4-phenyl-2- [2- (3,4,5-trimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

2- [5-fluoro-2- (4-methylpiperazin-1-yl) -benzylidene] -4-phenyl-thiomorpholin-3-one;

4-benzo [1,3] dioxol-5-yl-2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

2- [2- (4-t-butylpiperazin-1-yl) -benzylidene] -4- (3,4-dichlorophenyl) -thiomorpholin-3-one;

3- (3,4-dichlorophenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidin-4-one;

3- [4- (3,4-Dichlorophenyl) -3-oxo-thiomorpholin-2-ylidenemethyl] -6-dimethylamino-2- (4-methylpiperazin-1-yl) -benzonitrile ;

5- [2- (4-methylpiperazin-1-yl) -benzylidene] -2-phenylthiazolidin-4-one;

4- (3,4-dichlorophenyl) -2- [2- (3,4,5-trimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [5-methyl-2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

2- [4-Chloro-2- (4-methylpiperazin-1-yl) -benzylidene] -4- (3,4-dichlorophenyl) -thiomorpholin-3-one;

4- (3,4-difluorophenyl) -2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (2,4-difluorophenyl) -2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

2- [4-bromo-2- (4-methylpiperazin-1-yl) -benzylidene] -4- (3,4-dichlorophenyl) -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (1-methylpyrrolidin-2-ylmethoxy) -benzylidene] -thiomorpholin-3-one;

4- (3,5-Dichlorophenyl) -2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-difluorophenyl) -2- [2- (3,4,5-trimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (octahydropyrido [1,2-a] pyrazin-2-yl) -benzylidene] -thiomorpholin-3-one;

2- [2- (4-cyclopropylpiperazin-1-yl) -benzylidene] -4-pyridin-3-yl-thiomorpholin-3-one;

2- [2- (4-cyclopropylpiperazin-1-yl) -benzylidene] -4- (3,4-difluorophenyl) -thiomorpholin-3-one;

2- [2- (4-cyclopropylpiperazin-1-yl) -benzylidene] -4- (3,5-dichlorophenyl) -thiomorpholin-3-one;

4- (3,4-difluorophenyl) -2- [2- (2,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,5-Dichlorophenyl) -2- [2- (2,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-Dichlorophenyl) -2- [2- (3-methylaminopyrrolidin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-difluorophenyl) -2- [2- (2,4,5-trimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4-benzo [1,3] dioxol-5-yl-2- [2- (4-cyclopropylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -4- (4-fluorophenyl) -thiomorpholin-3-one;

4-benzo [1,3] dioxol-5-yl-2- [2- (2,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -4-phenylthiomorpholin-3-one;

4- (3,4-Dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (3-dimethylaminopyrrolidin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (3-dimethylaminopyrrolidin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-Dichlorophenyl) -2- [2- (4-methyl- [1,4] diazepan-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (2,4,6-trimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

2- [2- (4-cyclopropylpiperazin-1-yl) -benzylidene] -4- (3,4-dichlorophenyl) -thiomorpholin-3-one; And

Pharmaceutically acceptable salts of these compounds.

Other compounds of formula I are as follows:

5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidine-2,4-dione;

2- [2,4-Dibromo-6- (4-methylpiperazin-1-yl) -benzylidene] -4- (3,4-dichlorophenyl) -thiomorpholin-3-one;

4- (4-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene]-[1,4] oxazepan-3-one;

4- (4-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene]-[1,4,5] oxadiazepane-3-one;

4- (4-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene]-[1,4] thiazepan-3-one;

4- (3,4-Dichlorophenyl) -2- {2-[(2-dimethylaminoethyl) -methyl-amino] -benzylidene} -thiomorpholin-3-one;

4- (3,4-Dichlorophenyl) -2- [2- (1-methylpiperidin-4-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-Dichlorophenyl) -2- [2- (1,4-dimethylpiperidin-4-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-Dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholine-3,5-dione;

4- (3,4-Dichlorophenyl) -2- [2- (2-dimethylaminoethoxy) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (4-isopropylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (1-methylpyrrolidin-3-ylmethyl) -benzylidene] -thiomorpholin-3-one;

4- (3,4-Dichlorophenyl) -2- {2- [methyl- (1-methylpyrrolidin-2-ylmethyl) -amino] -benzylidene} -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- [2- (1-methylpyrrolidin-2-ylmethoxy) -benzylidene] -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- {2- [2- (1-methylpyrrolidin-2-yl) -ethyl] -benzylidene} -thiomorpholin-3-one;

1- (3,4-dichlorophenyl) -4-methyl-3- [2- (4-methylpiperazin-1-yl) -benzylidene] -piperazin-2-one;

4-Methyl-3- [2- (4-methylpiperazin-1-yl) -benzylidene] -1- (4-trifluoromethylphenyl) -piperazin-2-one;

1- (4-chlorophenyl) -4-methyl-3- [2- (4-methylpiperazin-1-yl) -benzylidene] -piperazin-2-one;

2- [2- (4-methylpiperazin-1-yl) -benzylidene] -4- (4-trifluoromethylphenyl) -morpholin-3-one;

2- [4-fluoro-2- (4-methylpiperazin-1-yl) -benzylidene] -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one;

2- [5-fluoro-2- (4-methylpiperazin-1-yl) -benzylidene] -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one;

2- {1- [2- (4-Methylpiperazin-1-yl) -phenyl] -ethylidene} -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one;

2- [2- (4-methylpiperazin-1-yl) -benzyl] -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one;

4- (4-Chlorophenyl) -6-methyl-2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;

3- (4-chlorophenyl) -2,2-dimethyl-5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidin-4-one;

4- (4-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene]-[1,4] oxazepan-3-one;

4- (4-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -4H- [1,4] thiazin-3-one;

1- (4-Chlorophenyl) -4,6,6-trimethyl-3- [2- (4-methylpiperazin-1-yl) -benzylidene] -piperazin-2-one;

1- (4-chlorophenyl) -4-methyl-3- [2- (4-methylpiperazin-1-yl) -benzylidene] -piperazin-2-one;

4- (4-Chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -morpholin-3-one;

3- (4-chlorophenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -oxazolidin-4-one;

3- (4-chlorophenyl) -2,2-dimethyl-5- [2- (4-methylpiperazin-1-yl) -benzylidene] -imidazolidin-4-one; And

3- (4-Chlorophenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -imidazolidin-4-one.

The invention also relates to intermediates of the formula (V):

Where

R ¹ to R ³ , R ⁶ to R ¹³ , G ⁷ to G ⁵ , X, B, E, Y, Z, g, j, k, m, n, p, q, r and t are as defined above .

Specific examples of preferred compounds of formula V are as follows:

4-benzyl-2- {hydroxy- [2- (4-methylpiperazin-1-yl) -phenyl] methyl} -thiomorpholin-3-one;

4- (3,4-dichlorobenzyl) -2- {hydroxy- [2- (4-methylpiperazin-1-yl) -phenyl] methyl} -thiomorpholin-3-one;

2- {hydroxy- [2- (4-methylpiperazin-1-yl) -phenyl] methyl} -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one;

2- {hydroxy- [2- (4-methylpiperazin-1-yl) -phenyl] methyl} -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2-{[2-fluoro-6- (4-methylpiperazin-1-yl) -phenyl] hydroxymethyl} -thiomorpholin-3-one;

4- (3,4-dichlorophenyl) -2- {hydroxy- [2- (4-methylpiperazin-1-yl) -phenyl] methyl} -morpholin-3-one;

2-{[2,4-Dibromo-6- (4-methylpiperazin-1-yl) -phenyl] -hydroxymethyl} -4- (3,4-dichlorophenyl) -thiomorpholine-3 -On; And

4- (3,4-Dichlorophenyl) -2- {hydroxy- [2- (4-methylpiperazin-1-yl) -phenyl] methyl} -thiomorpholin-3-one.

The invention also relates to hypertension, depression, systemic anxiety disorders, phobias (e.g., agoraphobia, social and simple panphobia), posttraumatic stress disorder, evasive personality disorder, premature ejaculation, premature ejaculation in mammals, preferably humans. Disorders (e.g. anorexia nervosa and anorexia nervosa), obesity, chemical dependence (e.g. alcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepine poisoning), cluster headaches, migraines, pain, Alzheimer's disease, obsessive compulsive disorder Disorders, panic disorders, memory disorders (e.g., dementia, forgetfulness and memory impairment associated with aging (ARCD)), Parkinson's disease (e.g., dementia caused by Parkinson's disease, neuroleptic-induced parkinsonism and delayed dyskinesia) Negative gastrointestinal disorders, including changes in endocrine disorders (e.g. hyperprolactinemia), vascular history (especially cerebral vessels), cerebellar ataxia, motility and secretion Selected from symptoms, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette syndrome, bald wall, bleeding, male erectile dysfunction, cancer (eg small cell lung cancer), chronic paroxysmal migraine, and headache associated with vascular disorders A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in an amount effective to treat or prevent the disorder or condition.

The present invention also provides an amount of formula (I) effective in treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Examples of such disorders and conditions are detailed in the above paragraphs.

The invention also relates to hypertension, depression (e.g., depression in cancer patients, depression in Parkinson's disease, depression after myocardial infarction, symptomatic depression under syndrome, depression in infertile women, depression in pediatrics in mammals, preferably humans). , Major depression, single episode depression, reproducible depression, depression inferred by child abuse and postpartum depression, systemic anxiety disorders, phobias (eg, agoraphobia, social phobia and simple fear), post-traumatic stress disorder, evasive personality Disorders, premature ejaculation, eating disorders (eg anorexia nervosa and anorexia nervosa), obesity, chemical dependence (eg alcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepine poisoning), cluster headaches, migraine headaches, pain , Alzheimer's disease, obsessive compulsive disorder, panic disorder, memory disorders (eg, memory disorders associated with dementia, forgetfulness and aging (ARCD)), Parkinson's disease (E.g., dementia caused by Parkinson's disease, neuroleptic-induced parkinsonism and delayed dyskinesia), endocrine disorders (e.g. hyperprolactinemia), vascular history (especially cerebral vessels), cerebellar ataxia, motility and Gastrointestinal disorders, including changes in secretion, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette syndrome, hair follicle wall, male wall, male erectile dysfunction, cancer (eg small cell lung cancer), chronic To treat or prevent a disorder or condition selected from headaches associated with paroxysmal migraine and vascular disorders, a compound of formula (I) or a pharmaceutical agent thereof in an amount effective for treating or preventing said disorder or condition in a mammal in need thereof. To an acceptable salt thereof.

The invention also relates to a mammal in need of such treatment or prevention in a mammal, preferably a human, in order to treat or prevent a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission. A method comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in an effective amount for the treatment or prevention of

The invention also relates to hypertension, depression (e.g., depression in cancer patients, depression in Parkinson's disease, depression after myocardial infarction, symptomatic depression under syndrome, depression in infertile women, depression in pediatrics in mammals, preferably humans). , Major depression, single episode depression, reproducible depression, depression inferred by child abuse and postpartum depression, systemic anxiety disorders, phobias (eg, agoraphobia, social phobia and simple fear), post-traumatic stress disorder, evasive personality Disorders, premature ejaculation, eating disorders (eg anorexia nervosa and anorexia nervosa), obesity, chemical dependence (eg alcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepine poisoning), cluster headaches, migraine headaches, pain , Alzheimer's disease, obsessive compulsive disorder, panic disorder, memory disorders (eg, memory disorders associated with dementia, forgetfulness and aging (ARCD)), Parkinson's disease (E.g., dementia caused by Parkinson's disease, neuroleptic-induced parkinsonism and delayed dyskinesia), endocrine disorders (e.g. hyperprolactinemia), vascular history (especially cerebral vessels), cerebellar ataxia, motility and Gastrointestinal disorders, including changes in secretion, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette syndrome, hair follicle wall, male wall, male erectile dysfunction, cancer (eg small cell lung cancer), chronic An amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, in an amount effective for treating or preventing a disorder or condition selected from headaches associated with seizure migraine and vascular disorders It relates to a pharmaceutical composition.

The present invention also provides an amount of a compound of formula (I) effective for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human, or a compound thereof It relates to a pharmaceutical composition comprising a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

The invention also relates to hypertension, depression (e.g., depression in cancer patients, depression in Parkinson's disease, depression after myocardial infarction, symptomatic depression under syndrome, depression in infertile women, depression in pediatrics in mammals, preferably humans). , Major depression, single episode depression, reproducible depression, depression inferred by child abuse and postpartum depression, systemic anxiety disorders, phobias (eg, agoraphobia, social phobia and simple fear), post-traumatic stress disorder, evasive personality Disorders, sexual dysfunction (e.g. premature ejaculation), eating disorders (e.g. anorexia nervosa and anorexia nervosa), obesity, chemical dependence (e.g. alcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepine poisoning), Cluster headaches, migraines, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders (eg, dementia, forgetfulness, and age associated with aging) History of disorder (ARCD), Parkinson's disease (e.g., dementia caused by Parkinson's disease, neuroleptic-induced parkinsonism and delayed dyskinesia), endocrine disorders (e.g. hyperprolactinemia), vascular history (especially cerebral vessels) ), Gastrointestinal disorders including cerebellar ataxia, changes in motility and secretion, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette syndrome, hair growth walls, walls, male erectile dysfunction, cancer ( An amount of a chemical formula effective in serotonin receptor antagonism or action in a mammal in need of such treatment or prevention, for the treatment or prevention of disorders or conditions selected from, for example, small cell lung cancer), headaches associated with chronic paroxysmal migraine and vascular disorders. A method comprising administering a compound of I or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human, in a mammal in need of such treatment or prevention. A method comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The present invention provides a method for treating or preventing a condition or disorder that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human, comprising: (a) a pharmaceutically acceptable carrier; (b) a compound of Formula (I) or a pharmaceutically acceptable salt thereof; And (c) the amount of the 5-HT reuptake inhibitor, preferably sertraline, or a pharmaceutically acceptable salt thereof, wherein the amount of the active compound (ie, the compound of formula I and the 5-HT reuptake inhibitor) In an amount effective to treat or prevent a disorder or condition).

The present invention is also directed to a mammal in need of such treatment or prophylaxis in order to treat or prevent a condition or disorder that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human. A compound of I or a pharmaceutically acceptable salt thereof; And (b) a 5-HT reuptake inhibitor, preferably cetralline, or a pharmaceutically acceptable salt thereof, wherein the amount of the active compound (ie, the compound of formula I and the 5-HT reuptake inhibitor) In an amount effective for treatment or prophylaxis).

The invention also relates to a mammal in need of such treatment or prophylaxis in order to treat or prevent a condition or disorder that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human. -HT _1A antagonist or a pharmaceutically acceptable salt thereof; And (b) the amount of each of the 5-HT _1D antagonist of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the active compound (ie, 5-HT _1A antagonist and 5-HT _1D antagonist) is used to treat or prevent the disorder or condition. In an amount effective at).

The invention also provides a method for treating or preventing a condition or disorder that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, preferably a human, comprising: (a) a 5-HT _1A antagonist or a pharmaceutically acceptable thereof salt; And (b) the amount of each of the 5-HT _1D antagonist of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the active compound (ie, 5-HT _1A antagonist and 5-HT _1D antagonist) is used to treat or prevent the disorder or condition. Effective amount for the present invention).

As used herein, the term "improvement of serotonergic neurotransmission" refers to the release of serotonin from presynaptic cells upon excitation which increases or improves the neuronal process by crossing the synapses to stimulate or inhibit postsynaptic cells.

As used herein, "chemical dependence" refers to an abnormal desire or desire or drug addiction for a drug. Such drugs are generally administered to an individual addicted by any of various means such as oral, parenteral, nasal or inhalation. Examples of chemical dependencies treatable by the methods of the invention are dependence on alcohol, nicotine, cocaine, heroin, phenolbarbitol and benzodiazepines (eg Valium, trade name). As used herein, "treatment of chemical dependence" is meant to relieve or alleviate this dependency.

The term "setralin" as used herein refers to (1S-cis) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, wherein It is represented by C ₁₇ H ₁₇ NCl ₂ and has the following structure:

Methods of synthesizing these compounds are described in US Pat. No. 4,536,518 assigned to Pfizer Inc. Setralin hydrochloride is useful as an antidepressant and anorexia antagonist and also for the treatment of depression, chemical dependence, anxiety, obsessive compulsive disorder, phobia, panic disorder, post traumatic stress disorder and premature ejaculation.

The present invention relates to novel aralkyl and aralkylidene heterocyclic lactams and imides, intermediates useful for their preparation, pharmaceutical compositions containing them and their medical uses. Compounds of the present invention include selective and antagonists of one or both of the serotonin 1 (5-HT ₁ ) receptor, specifically the 5-HT _1A receptor and the 5-HT _1D receptor. They are useful for the treatment or prevention of diseases involving migraine, depression and other 5-HT ₁ agonists or antagonists.

Compounds of formula (I) can be prepared according to the following schemes and descriptions. Unless stated otherwise, R ¹ to R ³ , R ⁶ to R ¹³ , G ¹ to G ⁷ , X, B, E, Y, Z, g, j, k, m, n, p, q, r and t and the compounds of formula (I) in the schemes and their descriptions are as defined above.

Where

Q is Br, X is not Br and I, R ¹ is G ² and R ⁶ is H.

Scheme 1 illustrates a method of synthesizing a compound of Formula I, wherein the dotted line represents a carbon-carbon double bond and R ¹ is a group of G ¹ , G ³ , G ⁴ , G ⁵ , G ⁶ or G ⁷ . In Scheme 1, a compound of Formula III wherein Q is a suitable leaving group (e.g., chloro, fluoro, bromo, mesylate, tosylate, etc.) is added to the general formula R ¹ H in the presence of a base, Hydrogen atom or a hydrogen atom on a nitrogen atom of G ¹ , G ³ , G ⁵ , G ⁶ or G ⁷ groups, R ¹ is a G ¹ , G ³ , G ⁴ , G ⁵ , G ⁶ or G ⁷ group) React with the compound to form the corresponding compound of formula II. The reaction is generally carried out at about 0 ° C. to about 140 ° C., preferably at about reflux temperature, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA) or N- In a polar solvent such as methyl-2-pyrrolidinone (NMP), preferably DMF. Suitable bases include anhydrous sodium carbonate (Na ₂ CO ₃ ), potassium carbonate (K ₂ CO ₃ ), sodium hydroxide (NaOH) and potassium hydroxide (KOH), as well as amines such as pyrrolidine, triethylamine and pyridine. Anhydrous potassium carbonate is preferred.

R ³ may be converted to a compound of formula I other than hydrogen by aldol condensation or Wittig reaction of the compound of formula II. For example, in the case of aldol condensation, a compound of formula (II) is reacted with a compound of formula (IV) in the presence of a base to form an aldol intermediate of formula (V) and to isolate it or to remove water in the same reaction step You can switch directly:

Formula V

One or more analytical techniques, such as thin layer chromatography (TLC) or mass spectrometry, can be used to analyze the degree of completion of conversion of the compound of formula (II) to the aldol compound of formula (I). In some cases it may be possible or desirable to isolate the intermediate of Formula (V). In this case, the compounds of formula (V) are converted to the compounds of formula (I) using water removal methods well known in the art, for example catalytic amounts of benzene- or p-toluene-sulfonic acid in preparation for the removal of the resulting water. The solution of the compound of formula V in the presence of can be converted to the compound of formula I by heating to reflux in a solvent such as benzene, toluene or xylene. Such water removal methods include the use of molecular sieves or Dean-Stark traps to isolate azeotropically produced water with solvents.

The aldol reaction is typically carried out at about -78 ° C to about 80 ° C in a polar solvent such as DMSO, DMF, tetrahydrofuran (THF), methanol or ethanol. Preferably this reaction is carried out in THF at about 25 ° C. Suitable bases for use in the aldol formation step include K ₂ CO ₃ , Na ₂ CO ₃ , sodium hydride (NaH), sodium methoxide, potassium tert-butoxide, lithium diisopropylamide pyrrolidine, and piperi Dean is included. Sodium hydride is preferred. Aldol condensation is described in " Modern Synthetic Reactions ", Herbert O. House, 2d. Edition, WA Benjamin, Menlo Park, California, 1972, pp. 629-682 and Tetrahedron , 38 (20), 1982, 3059.

A compound of formula (I) R ³ is not hydrogen, the compound of formula (II) as a starting material R ³ is hydrogen or -C (= O) R ¹³ (wherein R ¹³ is an alkyl or trifluoromethyl (C ₁ -C ₆₎ is methyl) is reacted with the compound of formula (IV) and, subsequently, if present -C (= O) 'the compound of formula (wherein L' R ¹³ and the formula R ³ -L reaction for removing groups is a leaving group and the above Q And the same as defined). This reaction is carried out with di (alkyl) ether, THF, DMF, DMA or DMSO, preferably DMF in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydride, potassium hydride, sodium hydroxide or potassium hydroxide, preferably sodium hydride. It may be carried out in the same solvent. The reaction temperature is about 0 ° C. to about 150 ° C., preferably about 25 ° C. to about reflux temperature of the solvent.

Alternatively, Helvetica Chimica Acta , 1963, 46 , 1580 and the compounds of formula IV can be converted to compounds of formula I by witig olefination as described below:

Thus, the compound of formula IV can be converted to the corresponding bromide of formula XI using standard bromination conditions and then treated with triphenylphosphine in anhydrous THF to form the intermediate of formula XII. The compound of formula (XII) is then treated with a strong base (eg aqueous Na ₂ CO ₃ ) to produce the corresponding phosphonium illide, which is then reacted with the appropriate intermediate of formula (II) to produce the compound of formula (I). Such transformations are described in A. Maercker, Organic Reactions , 1965, 14 , 270.

Compounds of formula (I), wherein the dotted lines are carbon-carbon single bonds, can be prepared by hydrogenating the corresponding compounds, where the dotted lines are carbon-carbon double bonds, using standard techniques well known in the art. See, eg, Catalytic Hydrogenation in Organic Synthesis , Paul Rylander, Academic Press Inc., San Diego, 1979, pp. 31-63, palladium on carbon (Pd / C), sulfuric acid in a suitable solvent such as methanol, ethanol, THF, dioxane or ethyl acetate at about 10 ° C. to about 60 ° C. under about 1 to 5 atmospheres. Using hydrogen gas (H ₂ ) using a catalyst such as palladium on barium (Pd / BaSO ₄ ), platinum on carbon (Pt / C), or tris (triphenylphosphine) rhodium chloride (Wilkinson catalyst) To reduce the double bond. Preference is given to using hydrogen pressure of 50 psi, 25 ° C., methanol and palladium on carbon. In this method also hydrogen isotopes (ie deuterium, tritium) can be introduced by replacing ¹ H ₂ with ² H ₂ or ³ H ₂ .

Another method using reagents such as ammonium formate and Pd / C in methanol at reflux temperature in an inert atmosphere (eg nitrogen or argon gas) is also effective for reducing the carbon-carbon double bond of the compound of formula (I). Another effective method involves the selective reduction of carbon-carbon bonds. This is accomplished using iodine or samarium iodide (SmI ₂ ) in methanol or ethanol at approximately room temperature, as described in Yanada, R, et al., Synlett ., 1995, pp 443-4. Can be performed.

Starting materials of formula III and IV are commercially available or well known in the art. For example, compounds of formula III wherein R ² is hydrogen can be readily purchased from commercial sources or can be prepared by the methods described in the chemical literature. Compounds of formula III can also be prepared from commercially available corresponding carboxylic acids or esters (ie compounds of formula III wherein R ² is OH or O-alkyl). Depending on the type of substituents Q and X of the compounds of formula XIII, one or more of various reducing agents and conditions may be used to reduce the acid or ester to the corresponding alcohol of formula XIII, wherein Q is as defined in formula III. :

Such reducing agents include sodium borohydride (NaBH ₄ ), sodium cyanoborohydride (NaCNBH ₃ ), lithium aluminum hydride (LiAlH ₄ ) and THF (in solvents such as methanol, ethanol, THF, diethyl ether and dioxane). Borane is included in BH ₃ · THF). The alcohol of formula XIII can be oxidized to the corresponding aldehyde of formula II using an optional oxidizing agent such as Jones reagent (hydrochloric acid (H ₂ CrO ₄ )), pyridinium chlorochromate (PCC) or manganese dioxide (MnO ₂ ). have. For such transformations, see Wiberg, KB, Oxidation in Organic Chemistry, Part A , Academic Press Inc., NY 1965, pp. 69-72.

Compounds of formula IV can be purchased commercially or prepared according to methods well known in the art. Examples of sources of various compounds of Formula IV are shown in Tables 1-3 below.

Compounds of formula IV wherein Y is -LMPQ, L is sulfur or oxygen, M and P are -CH ₂ -and Q is-(C = 0)-can be prepared according to the following method. The compounds of formula IV shown below are described in Meyers, JOC , 54 (17) , 4243 (1989), by Fickenscher, Arch. Pharm. , 307 , 520 (1976) or Cole et al ., J. Med. Chem. , 13 , 565 (1970), are prepared by reacting a compound of formula XXXI with an amine of formula R ³ NH ₂ according to the method described in detail:

Formula IV

Where

Y is -LMPQ, L is sulfur or oxygen, M and P are -CH _2- , and Q is-(C = O)-.

Anhydrides of Formula (XXXI) are diacids of Formula (XXX) according to the method described in Vogel, Textbook of Practical Organic Chemistry , 499-501 (4th edition, Longman House, London, United Kingdom, 1970). The compound can be prepared by reacting with acetic anhydride.

Where

L is sulfur or oxygen.

Compounds of formula XXX are commercially available or can be prepared according to the methods of Woodward and Eastman ( JACS , 68 , 2229 (1946)).

Compounds of formula IV wherein Y is -LMPQ, L and M are carbon, P is oxygen and Q is-(C = O)-can be prepared according to the following method. Compounds of formula IV shown below are described in Back et al ., Tet. Lett. , 2651-2654 (1977), are prepared from compounds of formula XXXIV. Compounds of formula XXXIV can be prepared according to the methods of Ksander et al., JOC, 42, (7), 1180-1185 (1997):

Formula IV

Where

Y is -LMPQ, L and M are CH ₂ , P is oxygen and Q is-(C = 0)-.

Compounds of formula IV wherein R ³ is hydrogen (compounds of formula IVA) can be alkylated using standard methods known to those skilled in the art to form the corresponding compounds where R ³ is not hydrogen, for example ( a) using a strong base / polar solvent system such as NaH / THF, NaH / DMF or n-butyllithium / THF (n-buLi / THF), from about -30 ° C. to about 5 minutes at about reflux of the solvent For about 24 hours, an anion of the compound of formula (IVA) is produced, and (b) this anion is of the formula R ³ L 'wherein L' is a leaving group such as chloro, bromo, iodo or mesylate Alkylation is carried out by treatment with alkylating agents. This process is shown below:

In the formula IVA R ³ is R ³ is hydrogen in the formula IVB is not hydrogen.

It is also possible to convert the compound of formula IVA to the compound of formula IVB using phase transfer catalysis conditions as described in Takahata et al., Heterocycles , 1979, 12 (11) , pp1449-1451.

Compounds of formula (IVB) wherein R ³ is aryl or heteroaryl are those of formula (IVA) in the presence of a copper (0) or copper (I) catalyst such as copper, copper-copper or copper bromide and a base such as sodium hydride, potassium carbonate or sodium carbonate The compounds may be prepared by reacting with an aryl or heteroaryl reagent of the formula R ³ L ′, where L ′ is a leaving group such as chloro, bromo or iodo. The reaction may be carried out without solvent or may be carried out in a polar solvent such as dimethylformamide or dimethylsulfoxide. This reaction is referred to as Ullmann condensation and is described by Yamamoto and Kurata in Chem. and Industry , 737-738 (1981).

Compounds of formula R ¹ H used in the preparation of intermediates of formula II are readily available or can be prepared using standard methods of organic synthesis known to those skilled in the art and modified from the methods disclosed in the chemical literature. have. For example, a compound of Formula R ¹ H, wherein R ¹ is G ¹ , can be prepared using commercially available N-tert-butoxycarbonyl piperazine (VI) using the following reaction procedure:

In a polar solvent such as acetone in the presence of an acid scavenger (e.g. sodium bicarbonate (NaHCO ₃ ), potassium bicarbonate (KHCO ₃ ), sodium carbonate (Na ₂ CO ₃ ) or potassium carbonate (K ₂ CO ₃ )), From 10 [deg.] C. to about reflux temperature of the solvent, the compound of formula VI is defined as R ⁶ L 'wherein L' is defined in the same way as Q above as leaving group and R ⁶ is (C ₁ -C ₆ ) (C ₁ -C ₄ ) alkyl, the aryl moiety is phenyl or naphthyl or heteroaryl- (CH ₂ ) _q , q is 0, 1, 2, 3 or 4 and the heteroaryl moiety is pyridyl, pyrimidyl , Benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl) to obtain an intermediate of formula (VII). The tert-butoxy-carbonyl group can be removed using HBr in acidic conditions such as acetic acid or trifluoroacetic acid until the reaction is judged complete.

As shown in Scheme 2, compounds of Formula II wherein R ¹ is tetrahydropyridine or piperidine (ie, a compound of Formula G ² ) and R ² is hydrogen may be prepared from a variety of commercially available 2-bromobenzaldehydes of It can manufacture. Referring to Scheme 2, first the compounds of formula III are converted into protected aldehydes of formula XIV, wherein P is a protected aldehyde or ketone moiety in its entirety by methods well known in the art. For example, 1,3-dioxolane derivatives of aldehydes are described in Cole, JE et al., J. Chem. Soc ., 1962, pp 244, can be prepared by refluxing a solution of 1,3-propanediol and an aldehyde of formula III in anhydrous benzene with a catalytic amount of p-toluenesulfonic acid. If R ² of formula III is not hydrogen, suitable protecting groups may be used to protect the ketone. Suitable protecting groups can be selected from many protecting groups depending on the presence and nature of substituent X. Examples of suitable protecting groups can be found in Greene, TW and P. Wuts, Protecting Groups in Organic Synthesis , John Wiley Sons, 2nd edition, New York, 1991. Most preferred protecting groups are catalytically non-hydrogenated protecting groups (eg 1,3-dioxolane), which compounds may optionally reduce the carbon-carbon double bonds of tetrahydropyridine of formula XVIA.

Subsequently, in the presence of a catalyst, the compound of formula (XIV) is converted to a vinyl hydride (e.g., 1-BOC-4-trimethylstannyl-1,2,5,6-tetrahydropyridine, wherein BOC is Butyloxycarbonyl)) to form the corresponding compound of formula XVIA:

Preferred catalysts are palladium [for example ((C ₆ H ₅ ) ₃ P) ₄ Pd or Pd ₂ (dba) ₃ , where dba is dibenzylideneacetone). The reaction may be carried out without solvent, suitable solvents are acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone, preferably dimethylformamide. The reaction is conveniently carried out at about 20 ° C to about 160 ° C, preferably at about 60 ° C to about 130 ° C. This reaction is described by Dowben, WG, "Palladium-catalyzed Vinylation of Organic Halides", Organic Reactions , Vol 27 , pp. 345-390, Dowben Edit, John Wiley Sons, Inc., New. York, New York, 1982].

Compounds of formula (XVIA) can be converted to compounds of formula (II) wherein R ¹ is tetrahydropyridine by removing an aldehyde or ketone protecting group. P, a protecting group for an aldehyde or ketone, can be prepared by stirring one or more solutions of the compound of formula XVI in 5% hydrochloric acid and THF for 20 hours at room temperature, for example, using one or more of the methods described in the documents mentioned above. Unprotected ketones or aldehydes of the formula -C (= 0) R ² can be converted.

Alternatively, the standard method known in the art, generally palladium on carbon, is used as catalyst to catalytically hydrogenate the tetrahydropyridine of Formula XVIA to form the corresponding compound of Formula XVIB. The compound may be converted to the compound of formula II wherein R ¹ is piperidine (G ² ). This reaction is typically carried out in the presence or absence of a protic such as acetic acid or hydrochloric acid in an inert solvent such as ethanol or ethyl acetate. Acetic acid is preferred. A protecting group on G ² (e.g., BOC) is stirred using, for example, one or more methods described in Grin's literature mentioned above, for example, compound of formula XVI and 3M hydrochloric acid in ethyl acetate for about 30 minutes at approximately room temperature. Can be removed. P, a protecting group for aldehydes or ketones, can be converted to unprotected ketones or aldehydes as mentioned above.

Compounds of formula (XIV) obtained from the reaction of Scheme 2 can also be used as alkyllithium reagents, such as n-butyllithium, secondary-butyllithium or tert-butyllithium, preferably in an inert solvent, as shown in Scheme 3. Treatment with n-butyllithium can form the intermediate lithium anion of Formula XVII. Suitable solvents for this reaction include, for example, ether or tetrahydrofuran, preferably tetrahydrofuran. The reaction temperature may be about -110 ° C to about 0 ° C. The intermediate lithium anion of formula (XVII) may be further reacted with a suitable electrophile (selected depending on the presence and nature of the substituent). Suitable electrophiles for use in preparing compounds of formula II wherein R ¹ is a G ² group include, for example, carbonyl derivatives or alkylating agents (eg 1-BOC-4-piperidone). If aldehydes or ketones are used as electrophiles, the hydroxyl groups must be removed from the intermediate of formula XVIII as shown below to form the corresponding compound of formula II:

R ¹ in Formula II is G ² .

This step can be carried out by one of several standard methods known in the art. Thiocarbonyl derivatives such as, for example, xanthate can be prepared and removed by free radical processes (both methods are known in the art). On the one hand, hydroxyl groups can be removed under acidic conditions, for example by using trifluoroacetic acid or boron trifluoride to reduce to a hydride source such as triethylsilane. This reduction reaction can be carried out without solvent or in a solvent such as methylene chloride. Alternatively, the hydroxyl group is converted to a suitable leaving group such as tosylate or chloride using standard methods known in the art, and the leaving group is then removed using a nucleophilic hydride such as lithium aluminum hydride. The latter reaction is typically carried out in an inert solvent such as ether or tetrahydrofuran. It is also possible to reduce the benzyl substituent by using a reducing agent. Suitable reducing agents include, for example, Raney nickel in ethanol and sodium or lithium in liquid ammonia. Another method used to remove hydroxyl groups is to first formulate the alcohol of formula XVIII using a reagent such as Burges salt (see J. Org. Chem ., 1973, 38 , 26). Dehydration to be the olefin of XVIA is followed by catalytic hydrogenation of the double bonds using a catalyst such as palladium on carbon under standard conditions. The alcohol may also be treated with an acid such as p-toluenesulfonic acid to dehydrate to form an olefin.

A compound of Formula II wherein R ¹ is G ² and R ⁶ is hydrogen is reacted with a compound of Formula R ⁶ L ′ as described in Scheme 1 to prepare a compound of Formula VII, where R ¹ is G ² and R ⁶ This hydrogen can be converted to the corresponding compound of formula II.

Unless otherwise stated, the pressure of each of the above reactions is not critical. Generally the reaction is carried out at about 1 to about 3 atmospheres, preferably at ambient pressure (about 1 atmosphere).

Compounds of formula (I) having basic properties can form a wide variety of different salts with various inorganic and organic acids. Although such salts are pharmaceutically acceptable for administration to animals, in practice they are initially isolated from the reaction mixture as pharmaceutically unacceptable salts and then converted back to the free base compound by treatment with alkaline reagents. It is often desirable to convert this free base into a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of the invention can be readily prepared by treating the base compounds of the invention with substantially equal amounts of selected mineral or organic acids in an aqueous solvent medium or a suitable organic solvent such as methanol or ethanol. The solvent is evaporated carefully to get the desired solid salt.

Acids used to prepare pharmaceutically acceptable acid addition salts of the base compounds of the present invention are nontoxic acid addition salts, ie salts containing pharmaceutically acceptable anions such as hydrochloride, hydrobromide, hydroiodide , Nitrates, sulfates or bisulfates, phosphates or acid phosphates, acetates, lactates, citrate or acid citrates, tartrates or bitartrates, succinates, maleates, fumarates, gluconates, saccharides, benzoates , Methanesulfonate and pamoate [ie, 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)] salts.

Compounds of formula (I) having acidic properties, for example compounds of formula (I) in which R ³ is COOH or tetrazole residues, can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, in particular sodium and potassium salts. All of these salts are prepared by conventional methods. Base compounds used as reagents to prepare pharmaceutically acceptable base salts of the present invention are bases which form non-toxic base salts with the desired acidic compounds of formula (I) described herein. Such non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium. Such salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating to dry the resulting solution, preferably under reduced pressure. On the one hand, they can also be prepared by mixing with an alkanolic solution of an acidic compound and the desired alkali metal alkoxide, followed by evaporation to dryness of the resulting solution in the same manner as the previous method. Alternatively, it is preferable to use stoichiometric amounts of reagents to ensure completion of the reaction and to obtain maximum yield.

The compounds of formula (I) and their pharmaceutically acceptable salts (hereinafter collectively referred to as "active compounds") are useful for psychotherapy and are effective in serotonin 1A (5-HT _1A ) and / or serotonin 1D (5-HT _1D ) receptors. Agonists and / or antagonists. The active compounds herein include hypertension, depression, systemic anxiety disorders, phobias (e.g., agoraphobia, social phobias and simple phobias), post-traumatic stress disorders, evasive personality disorders, sexual dysfunctions (e. For example anorexia nervosa and bulimia nervosa, obesity, chemical dependence (eg alcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepines intoxication), cluster headaches, migraine headaches, pain, Alzheimer's disease, obsessive-compulsive impulses Disorders, panic disorders, memory disorders (e.g., dementia, forgetfulness and memory impairment associated with aging (ARCD)), Parkinson's disease (e.g., dementia caused by Parkinson's disease, neuroleptic-induced parkinsonism and delayed dyskinesia) Negative symptoms of gastrointestinal disorders, including changes in endocrine disorders (e.g. hyperprolactinemia), vascular history (especially cerebral vessels), cerebellar ataxia, motility and secretion It is useful in the treatment of premenstrual syndrome, fibromyalgia syndrome, stress urinary incontinence, Tourette syndrome, hair growth wall, wall, male erectile dysfunction, cancer (eg small cell lung cancer), chronic paroxysmal migraine and vascular disorders.

The affinity of the compounds of the invention for various serotonin-1 receptors can be determined using standard radioligand binding assays as described in the literature. 5-HT _1A affinity can be measured according to the method described in Hoyer et al., Brain Res ., 1986, 376 , 85. 5-HT _1D affinity can be measured according to the methods described in Heuring and Peroutka, J. Neurosci ., 1987, 7 , 894.

The following procedure can determine the in vitro activity of a compound of the invention at the 5-HT _1D binding site. Bovine tail tissue is homogenized and suspended in 20 volumes of buffer at pH 7.7 containing 50 mM TRIS hydrochloride (tris [hydroxymethyl] aminomethane hydrochloride). The homogenate is then centrifuged at 45,000 G for 10 minutes. Discard the supernatant and resuspend the remaining pellets in about 20 volumes of 50 mM TRIS hydrochloride (HCl) buffer at pH 7.7. This suspension is then preincubated at 37 ° C. for 15 minutes, the suspension is again centrifuged at 45,000 G for 10 minutes and the supernatant is discarded. The resulting pellet (approximately 1 g) is resuspended in 150 ml of a buffer of 15 mM TRIS hydrochloride at pH 7.7 containing 10 μM pagiline and 4 mM calcium chloride (CaCl ₂ ) and 0.01% ascorbic acid. The suspension is kept on ice for at least 30 minutes before use.

Inhibitors, controls or vehicles are then incubated according to the following procedure. 50 µl solution of 20% dimethyl sulfoxide (DMSO) / 80% distilled water, 0.01% ascorbic acid at pH 7.7 containing 10 μM pagiline and 4 μM calcium chloride, 8 n-hydroxy-DPAT (dipropylaminotetraline at 100 nM) ) And 200 [mu] l of tritiated 5-hydroxytrytamine (2 nM) in a buffer of 50 mM TRIS hydrochloride at pH 7.7 containing 100 nM mesulergine. 750 μl of bovine tail tissue is added to this mixture and the resulting suspension is stirred to obtain a homogeneous suspension. This suspension is then incubated for 30 minutes at 25 ° C. in a stirred water bath. After the incubation is complete, the suspension is filtered using a glass fiber filter (eg Whatman GF / B-Filter ^TM ). The pellet is then washed three times with 4 ml of a buffer of 50 mM TRIS hydrochloride at pH 7.7. The pellet is then placed in a scintillation vial with 5 ml scintillation fluid (Aquasol 2, trade name) and allowed to stand overnight. Inhibition rates can be calculated for each dose of compound. IC ₅₀ values can then be calculated from the inhibition rate.

The following procedure can determine the 5-HT _1A binding capacity of the compounds of the present invention. Rat brain cortical tissue is homogenized and divided into 1 g lots of samples and diluted with 10 volumes of 0.32 M sucrose solution. The suspension is then centrifuged at 900 G for 10 minutes, the supernatant is separated and recentrifuged at 70,000 G for 15 minutes. Discard the supernatant and resuspend the pellet in 10 volumes of 15 mM TRIS hydrochloride buffer at pH 7.5. This suspension is then incubated at 37 ° C. for 15 minutes. After incubation is complete, the suspension is again centrifuged at 70,000G for 15 minutes and the supernatant is discarded. The resulting tissue pellets are resuspended in a buffer of 50 mM TRIS hydrochloride at pH 7.7 containing 4 mM calcium chloride and 0.01% ascorbic acid. Tissue is stored at -70 ° C until the experiment is ready. Immediately before use, thaw the tissue, dilute with 10 μm of pagiline and keep on ice.

The tissue is then cultured according to the following procedure. 50 μl of the control, inhibitor or vehicle (1% DMSO final concentration) are prepared in varying amounts. To this solution is added 200 μl of a final concentration of 1.5 nM tritiated DPAT in a buffer of 50 mM TRIS hydrochloride at pH 7.7 containing 4 mM calcium chloride, 0.01% ascorbic acid and pagiline. 750 μl of tissue is added to the solution and the suspension thus obtained is stirred to obtain a homogeneous suspension. This suspension is then incubated for 30 minutes at 37 ° C. in a stirred water bath. The solution is then filtered and washed twice with 4 ml of 10 mM TRIS hydrochloride at pH 7.5 containing 154 mM sodium chloride. Inhibition rates can be calculated for the dose of each compound, control or vehicle. IC ₅₀ values can then be calculated from the inhibition rate.

Compounds of formula (I) of the present invention described in the Examples below were analyzed for 5-HT _1A and 5-HT _1D affinity using the methods described above. All these test compounds exhibited IC ₅₀ of less than exhibited an IC ₅₀ of less than 0.60μM for the 5-HT _1D affinity for the 5-HT _1A affinity 1.0μM.

The following procedure can be used to determine the action and antagonistic activity of the compounds of the invention on 5-HT _1A and 5-HT _1D receptors using single saturation concentrations. Whereas the male Hartley guinea pigs are obtained by slicing and dissecting the 5-HT _1A receptor from the hippocampus, the 5-HT _1D receptor is sliced to 350 mM using a Mcllwain tissue chopper and sliced from suitable pieces. Obtained by separating black matter. Individual tissues are homogenized in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using a manual glass-Teflon® homogenizer and centrifuged at 35,000 × g for 10 minutes at 4 ° C. The pellet is resuspended in 100 mM HEPES buffer containing a final protein concentration of 20 mg (hippocampus) or 5 mg (chromatin) per tube and 1 mM EGTA (pH 7.5). The reaction mixture in each in vitro was made up of 2.0 mM MgCl ₂ , 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mM phosphocreatin, 0.31 mg / ml creatine phosphokinase, 100 μM GTP and 0.5 to 1 microcury [ ³² The reagents were added to contain P] -ATP (30 Ci / mmol: NEG-003-New England Nuclear). Cultivation is initiated by adding tissue to a siliconized microfuge test tube at 30 ° C. over 15 minutes (3 batches). Each test tube contains 20 μl tissue, 10 μl drug or buffer (10 times final concentration), 10 μl 32 nM agonist or buffer (10 times final concentration), 20 μl forskolin (final concentration 3 μM). ) And 40 μl of the reaction mixture described above. Monitor the recovery of cAMP from the column by adding 45 mM ATP solution containing 100 μl of 2% SDS, 1.3 mM cAMP, 40,000 dpm [ ³ H] -cAMP (30 Ci / mmol: NET-275-New England Nuclear) The culture was terminated by doing so. Separation of [ ³² P] -ATP and [ ³² P] -cAMP is performed using the method of Salomon et al., Analytical Biochemistry , 1974, 58 , 541-548. Liquid scintillation counting is used to quantify radioactivity. Maximum inhibition is defined as 10 μM (R) -8-OH-DPAT for the 5-HT _1A receptor and 320 nM 5-HT for the 5-HT _1D receptor. Inhibition rate by the test compound is calculated in relation to the inhibitory effect of (R) -8-OH-DPAT for the 5-HT _1A receptor or in relation to the inhibitory effect of 5-HT on the 5-HT _1D receptor. The reversal of agonist-induced inhibition of forskolin-stimulated adenylate cyclase activity is calculated in relation to the 32 nM agonist effect.

Compounds of the invention can be tested for in vivo activity against antagonism of 5-HT _1D agonist-induced hypothermia in guinea pigs according to the following procedure.

Male Hartley guinea pigs weighing 250 to 275 g on arrival and 300 to 600 g on test are obtained from the Charles River. Guinea pigs are confined under standard laboratory conditions with a mining schedule from 7 am to 7 pm for at least 7 days prior to testing. Randomly eat food and water until the test.

Compounds of the invention can be administered as a solution in a volume of 1 ml / kg. The vehicle used depends on the solubility of the compound. Typically test compounds were prepared using [3- (1-methylpyrrolidin-2-ylmethyl) -1H-indol-5yl]-(3-nitropyridin-3-yl) -amine (June 10, 1993). 5-HT agents, such as those described in PCT Publication No. WO93 / 11106, are administered orally 6 minutes prior to subcutaneous administration at 5.6 mg / kg or subcutaneously at 0 minutes. Before reading the body temperature for the first time, put each guinea pig in a transparent plastic shoe box with sawdust on the bottom of a metal grid and let it get used to the environment for 30 minutes. The body temperature of each animal is then read and returned to the same shoe box. Hold each animal firmly with one hand for 30 seconds before measuring each body temperature. Read the temperature on a digital thermometer with a small animal probe. The probe is made of semi-flexible nylon and has an epoxy tip. The temperature probe is inserted 6 cm deep into the rectum and left for 30 seconds or until a stable body temperature is obtained. Then record the temperature.

In the oral administration screening experiment, read the “prodrug” baseline body temperature at −90 minutes, body temperature at −60 minutes for the test compound and body temperature at additional −30 minutes. The 5-HT _1D antagonist is administered at 0 minutes and the temperature is read after 30, 60, 120 and 240 minutes.

In a subcutaneous injection screening experiment, a "prodrug" baseline body temperature is read at -30 minutes. The test compound and the 5-HT _1D antagonist are administered simultaneously and the temperature is read after 30, 60, 120 and 240 minutes.

Data are analyzed in two ways, repeated measures according to Newman-Keuls post hoc analysis.

In contracting isolated saphenous vein fragments in dogs, the present invention can evaluate the compounds of the invention as therapeutic agents for migraines by testing the extent to which the active compounds mimic sumatriptan (Humphrey, PPA). See Br. J. Pharmacol ., 94 , 1128 (1988). This effect can be blocked by known serotonin antagonist methiothepin. Sumatriptan is known to be useful for the treatment of migraine headaches and can selectively increase carotid artery resistance in anesthetized dogs. Pharmacological evidence for sumatriptan efficacy is given by Fenwick, W. et al ., Br. J. Pharmacol ., 96 , 83 (1989).

Serotonin 5-HT ₁ antagonist activity was described in 5-HT _1A receptor experiments using rat cortex as receptor source and [ ³ H] -8-OH-DPAT as radioligand (Huer, Di et al. Eur. J. Pharm ., 118 , 13 (1985)) and as described in 5-HT _1D receptor experiments using bovine tail as receptor source and [ ³ H] serotonin as radioligand. (See Heuring RE and Peroutka, SJ, J. Neuroscience , 7 , 894 (1987)). In vivo receptor binding assays. All of the active compounds tested showed IC ₅₀ of 1 μM or less in all assays.

Compounds of formula (I) may be used in combination with one or more other therapeutic agents, for example tricyclic antidepressants (e.g. amitriptyline, dotieppin, doxepin, trimipramine, buturiphylline, clomipramine, desipramine, Pramin, ifrindol, lofepramine, notiptiline or protriptyline), monoamine oxidase inhibitors (e.g. isocarboxazide, phenelzin or trinylcyclopramine) or 5-HT reuptake inhibitors ( Different antidepressants and / or dopaminergic antiparkinsonisms (e.g. levodopa, preferably peripheral dicarboxylase inhibitors (e.g. bencerazide or carbides) such as, for example, fluvoxamine, setraline, fluoxetine or paroxetine In combination with a dopamine agonist (eg bromocriptine, lisuride or pergolide). It is to be understood that the present invention includes the use of a compound of formula (I) or a physiologically acceptable salt thereof or solvate thereof in combination with one or more other therapeutic agents.

Compounds of formula (I) and pharmaceutically acceptable salts thereof are 5-HT reuptake inhibitors (e.g. fluvoxamine, setraline, fluoxetine or paroxetine), preferably setraline or a pharmaceutically acceptable salt thereof or Combinations with polymorphs (a combination of a compound of Formula I and a 5-HT reuptake inhibitor herein referred to herein as an "active combination") are useful for psychotherapy, and can be treated or prevented by enhancement of serotonin neurotransmission. Disabling disorders [e.g. hypertension, depression, systemic anxiety disorders, phobias, post-traumatic stress disorders, evasive personality disorders, sexual dysfunction, eating disorders, obesity, chemical dependence, cluster headaches, migraines, pain, Alzheimer's disease, Obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, forgetfulness and memory impairment associated with aging), Parkinson's disease (e.g., dementia caused by Parkinson's disease, neuroleptic-induced) Parkinsonism and delayed dyskinesia), endocrine disorders (such as hyperprolactinemia), vasculature (especially cerebral vessels), cerebellar ataxia, gastrointestinal disorders including changes in mobility and secretion, chronic paroxysmal migraine and blood vessels Can be used to treat or prevent headaches associated with the disorder.

Serotonin (5-HT) reuptake inhibitors, preferably serraline, are partially depressive in mammals, including humans, because they have the ability to block synaptosome uptake of serotonin; Chemical dependence; Anxiety disorders including panic disorder, systemic anxiety disorder, agoraphobia, simple fear, social fear and post-traumatic stress disorder; Positive activity in the treatment of obsessive-compulsive disorder, evasive personality disorder and premature ejaculation.

U.S. Patent No. 4,536,518 describes the synthesis of setraline, as a pharmaceutical composition and as an antidepressant, which is incorporated herein by reference in its entirety.

The activity of the active combination as an antidepressant and its associated pharmacological properties are described in the nose, as described in Koe, B, et al., Journal of Pharmacology and Experimental Therapeutics, 226 (3), 686-700 (1983). The same may be determined according to the method described in the following (1) to (4). Specifically, (1) studying the drug's ability to affect the ability of the mouse to escape from a swimming tank (Porsolt mouse “abandon behavior” test); (2) study the drug's ability to cause 5-hydroxyliptophan-induced behavioral symptoms in vivo in mice; (3) study the ability of a drug to antagonize the serotonin-depleting activity of p-chloroamphetamine hydrochloride in vivo in rat brain; (4) The activity of the drug can be determined by studying its ability to block the uptake of serotonin, norepinephrine and dopamine by synaptosome rat brain cells in vitro. The ability of an active combination to eliminate reserpin hypothermia in vivo in mice can be determined according to the methods described in US Pat. No. 4,029,731.

The compositions of the present invention can be formulated using one or more pharmaceutically acceptable carriers in a conventional manner. Thus, the active compounds of the present invention may be formulated for oral, buccal, nasal, parenteral (eg intravenous, intramuscular or subcutaneous) or rectal administration or in forms suitable for inhalation or aeration.

For oral administration, the pharmaceutical composition may comprise a binder (eg pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); Fillers (eg lactose, microcrystalline cellulose or calcium phosphate); Lubricants (eg magnesium stearate, talc or silica); Disintegrants (eg potato starch or sodium starch glycolate); Or in the form of tablets or capsules prepared, for example, by conventional means, together with pharmaceutically acceptable excipients such as wetting agents (eg sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may also be provided as a dry product for use in water or other suitable vehicle prior to use. Such liquid preparations may be prepared by suspending agents (for example sorbitol syrup, methyl cellulose or hydrogenated edible fats); Emulsifiers (eg lecithin or acacia); Non-aqueous vehicles (eg almond oil, oil esters or ethyl alcohol); And pharmaceutically acceptable additives such as preservatives (eg methyl or propyl p-hydroxybenzoate or sorbic acid).

For nasal administration, the compositions may take the form of tablets or lozenges prepared by conventional means.

The active compounds of the present invention may also be formulated for parenteral administration by injection, including conventional catheter insertion or infusion. Injectable preparations may be presented in unit dosage form, eg, in ampoules or in multiple dose containers, with a preservative. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulation agents such as suspending agents, stabilizers and / or dispersants. On the one hand, the active ingredient may be in powder form for use in a suitable vehicle, eg, sterile pyrogen-free distilled water, prior to use.

The active compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.

For nasal or inhalation administration, the active compounds of the present invention are conveniently delivered in the form of solutions or suspensions, usually in pump spray containers, which can be squeezed or pumped by the patient, or are dichlorodifluoromethane, trichlorofluoro It is provided as an aerosol spray provided from a pressurized vessel or spray using a suitable propellant such as romethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the unit dosage can be determined by providing a valve to deliver a metered amount. The pressurized vessel or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (for example made of gelatin) for use in an inhaler or insufflator can be formulated to contain a powder mixture of a suitable powder base such as lactose or starch and a compound of the invention.

When the active compound of the present invention is administered orally, parenterally or orally to an average adult for the treatment of the above-described conditions (eg depression), the dosage is 0.1 to 200 mg / kg of active ingredient per unit dose. For example, one to four times daily.

Aerosol formulations for the treatment of the aforementioned conditions of the average adult (eg migraine) are preferably prepared such that a "puff" or a metered dose of the aerosol contains 20 μg to 1000 μg of the compound of the invention. . The total daily dose of aerosol is 100 μg to 10 mg. For example, one, two or three doses may be administered two, three, four or eight times daily.

In connection with the use of the active compounds of the invention with a 5-HT reuptake inhibitor, preferably cetralline, for the treatment of a subject with any of the conditions described above, these compounds are pharmacologically acceptable according to the aforementioned routes It is to be understood that administration can be with a carrier, and that such administration can take place one or several times. More particularly, the active combinations can be administered in a variety of different formulations, that is, they are combined with various pharmaceutically acceptable inert carriers, tablets, capsules, lozenges, troches, hard candy, powders, sprays, aqueous suspensions, injectable solutions , Elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media, various non-toxic organic solvents, and the like. Moreover, such oral pharmaceutical preparations are suitably sweetened and / or flavored using various materials conventionally used for sweetening and / or flavoring purposes. Generally, compounds of formula (I) are present in such formulations at a concentration of about 0.5 to about 90 weight percent based on the total composition, ie, in an amount sufficient to provide the desired unit dosage, a 5-HT reuptake inhibitor, Preferably the setralin is present in such formulations at a concentration of about 0.5 to about 90 weight percent of the total composition, ie, in an amount sufficient to provide the desired unit dosage.

When oral, parenteral, rectal or oral administration of an active compound of the present invention in an active combination formulation (an agent containing the active compound of the present invention and a 5-HT reuptake inhibitor) for the treatment of the above-mentioned conditions to an average adult The daily dosage shown is about 0.01 to about 2000 mg, preferably about 0.1 to about 200 mg of the active ingredient of formula I per unit dose, for example 1 to 4 times daily.

The suggested daily dosage for oral, parenteral or oral administration of 5-HT reuptake inhibitors, preferably cetralline, in active combination formulations to the average adult for the treatment of the conditions described above is 5-HT reuptake per unit dose. Inhibitors are administered from about 0.1 to about 2000 mg, preferably from about 1 to about 200 mg, for example 1 to 4 times daily.

When orally, parenterally or orally administering an active combination formulation to an average adult for the treatment of the conditions described above, the preferred dosage ratio of cetralline in the active combination formulation to the active compound of the invention is about 0.00005 to about 20,000, preferably About 0.25 to about 2,000.

Aerosol formulations for the treatment of the aforementioned conditions of average adults preferably contain about 0.01 μg to about 100 mg, preferably about 1 μg to about 10 mg, of the active compound of the present invention or a puff or each metered dose of the aerosol. It is made to. Administration can be several times a day, for example two, three, four or eight daily doses of one, two or three doses each time.

Aerosol formulations for the treatment of the above-mentioned conditions of the average adult are preferably prepared such that the puff or each metered dose of the aerosol contains a 5-HT reuptake inhibitor, preferably about 1 mg to about 200 mg of seralin. Administration can be several times a day, for example two, three, four or eight daily doses of one, two or three doses each time.

As mentioned above, 5-HT reuptake inhibitors, preferably setraline, can be used in combination with a compound of formula (I) for therapeutic use as an antidepressant. In general, such antidepressant compositions containing 5-HT reuptake inhibitors, preferably cetralline and a compound of Formula I, typically contain from about 0.01 to about 100 mg of 5-HT reuptake inhibitor per kilogram of body weight per day. , Preferably, about 0.1 to about 10 mg of ceralin, preferably ceralin; And from about 0.001 to about 100 mg, preferably from about 0.01 to about 10 mg, per kg of body weight per day, but such dosage will vary depending on the condition of the patient to be treated and the specific route of administration selected. Can be.

The following examples illustrate the preparation of the compounds of the present invention. Melting point is uncorrected. NMR data are recorded in parts per million (δ) and reference is made to the deuterium lock signal from the sample solvent (unless otherwise stated deuterium chloroform). Non-rotationality was measured at room temperature using sodium D line (589 nm). Commercially available reagents were used without further purification. THF means tetrahydrofuran. DMF means N, N-dimethylformamide. Chromatography refers to column chromatography using silica gel of 32 to 63 μm and carried out under nitrogen pressure conditions (flash chromatography). Room temperature or room temperature means 20-25 degreeC. All non-aqueous reactions are carried out under nitrogen atmosphere for maximum yield and for convenience. Concentration under reduced pressure means using a rotary evaporator.

Example 1: 3- (4-chlorobenzyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -imidazolidine-2,4-dione

In a flame-dried flask under nitrogen atmosphere, sodium hydride (43 mg, 1.07 mmol, 60% oil dispersion) was washed with hexanes, treated with tetrahydrofuran (THF) (8 mL), and then 3- (4- Treated with chlorobenzyl) -imidazolidine-2,4-dione (235 mg, 1.04 mmol) and 2- (4-methylpiperazin-1-yl) -benzaldehyde (209 mg, 1.02 mmol), further THF 2 Treated with ml. After the mixture was refluxed overnight, the solvent was removed and the residue was treated with aqueous ammonium chloride and aqueous sodium bicarbonate to adjust the pH to 8 and then extracted with methylene chloride. The organic extract was washed with aqueous sodium chloride, dried and concentrated in vacuo to yield a yellow foam. The foam was crystallized from hot ethyl acetate: hexanes to give 240 mg (57%) of solids.

Melting point 185 to 187 ° C. Mass spectrum 411 (M ⁺¹ ). ¹ H NMR (CDCl ₃ ) δ9.45 (1H, s), 7.37-7.24 (4H, m), 7.16-7.09 (2H, m), 6.72 (1H, s), 4.72 (2H, s), 3.02 ( 4H, br s), 2.34 (3H, 2). Elemental Analysis for C ₂₂ H ₂₃ N ₄ O ₂ Cl · 0.5 H ₂ O—calc. C 62.93, H 5.76, N 13.34. Found: C 63.33, H 5.58, N 13.58.

Except as noted, the following examples were carried out in a similar manner to Example 1.

Example 2: 3- (4-chlorophenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -imidazolidine-2,4-dione

Melting point 193 to 193.5 ° C. Mass spectrum 397 (M ⁺¹ ). Elemental Analysis for C ₂₁ H ₂₁ N ₄ O ₂ Cl · 0.5 CH ₃ CN—calculated: C 63.31, H 5.43, N 15.10. Found: C 62.93, H 5.50, N 15.10.

Example 3: 3- (4-chlorobenzyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidine-2,4-dione hydrochloride hydrate

Melting point 240 to 242 ° C. Mass spectrum 428 (M ⁺¹ ). Elemental Analysis for C ₂₂ H ₂₂ N ₃ O ₂ SCl.HCl.0.25 H ₂ O—calc. C 56.35, H 5.05, N 8.96. Found: C 56.18, H 5.03, N 8.70.

Example 4: 4-benzyl-2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one

Melting point 106 to 108 ° C. Mass spectrum 394 (M ⁺¹ ). Elemental Analysis for C ₂₃ H ₂₇ N ₃ OS—calculated: C 70.20, H 6.91, N 10.68. Found: C 70.19, H 6.99, N 10.72. ¹ H NMR (CDCl ₃ ) δ8.10 (1H, s), 7.64 (1H, dd), 7.53-7.26 (6H, m), 7.08-6.97 (2H, m), 4.80 (2H, s), 3.69 ( 2H, sym m), 3.01 (4H, t), 2.88 (2H, sym m), 2.63 (4H, br s), 2.38 (3H, s).

Example 5: 4- (3,4-dichlorobenzyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one hydrochloride dihydrate

Melting point 90 to 115 ° C. Mass spectrum 462 (M ⁺¹ ). Elemental Analysis for C ₂₃ H ₂₅ N ₃ OSCl ₂ HCl 2 H ₂ O—calc. C 51.64, H 5.65, N 7.86. Found: C 51.83, H 5.76, N 7.64.

Example 6: 5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidine-2,4-dione hemihydrate

Yellow solid, Melting point 105 DEG C (decomposition). Mass spectrum 304 (M ⁺¹ ). Elemental Analysis for C ₁₅ H ₁₇ N ₃ O ₂ S0.5 H ₂ O—calc. C 57.67, H 5.81, N 13.45. Found: C 57.81, H 6.48, N 13.20. ¹ H NMR (CDCl _3, 400 MHz) δ8.05 (1H, s), 7.68 (1H, d), 7.36 (1H, dt), 7.12-7.03 (2H, m), 3.12-3.02 (5H, m) , 2.71 (4H, broad singlet), 2.41 (3H, singlet).

Example 7: 3- (4-Chlorophenyl) -5- [2- (4-methylpyrazin-1-yl) -benzylidene] -thiazolidine-2,4-dione hydrochloride hemihydrate

In a flame-dried flask under a nitrogen atmosphere, 3- (4-chlorophenyl) -thiazolidine-2,4-dione (158 mg, 0.694 mmol), 2- (4-methylpiperazine-) in 1 ml glacial acetic acid A mixture of 1-yl) -benzaldehyde (142 mg, 0.694 mmol) and sodium acetate (171 mg, 2.08 mmol) was heated to reflux for about 6 hours and then cooled to room temperature. Saturated aqueous sodium carbonate (Na ₂ CO ₃ ) was added until the pH was about 10, and then the mixture was extracted several times with methylene chloride. The organic layer was washed with brine and saturated sodium chloride, dried and evaporated to give a brown solid, which was recrystallized from ethyl acetate.

Melting point 187-189 ° C. Elemental Analysis for C ₂₁ H ₂₀ N ₃ O ₂ ClS- Calcd: C 60.94, H 4.87, N 10.15. Found: C 60.57, H 4.95, N 10.00.

The compound (56 mg) was treated with diethyl ether saturated with hydrogen chloride gas and the product was recrystallized from hot ethanol to give solid 3- (4-chlorophenyl) -5- [2- (4-methylpiperazin-1- 54 mg of I) -benzylidene] -thiazolidine-2,4-dione-hydrochloride hemihydrate was obtained; Melting point 254-258 ° C.

Elemental Analysis for C ₂₁ H ₂₀ N ₃ O ₂ ClS-HCl0.5 H ₂ O- Calcd: C 54.90, H 4.83, N 9.15. Found: C 55.07, H 5.01, N 8.78. ¹ H-NMR (DMSO-d ₆ ) δ10.84 (1H, br s), 7.60 (2H, d), 7.52-7.45 (4H, m), 7.24 (2H, t), 3.53-3.05 (8H, m ), 2.80 (3H, s).

Except as noted, the following examples were carried out in a similar manner to Example 7.

Example 8: 3- (4- [trifluoromethyl] -phenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidine-2,4-dione hydro Chloride dihydrate

Melting point 159-177 ° C. Mass spectrum 448 (M ⁺¹ ). Elemental Analysis for C ₂₂ H ₂₀ N ₃ O ₂ SF ₃ HCl 2 H ₂ O—calc. C 50.82, H 4.85, N 8.08. Found: C 51.04, H 4.66, N 8.01.

Example 9: 2- [2- (4-methylpiperazin-1-yl) -benzylidene] -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one hydrochloride trihydrate

Melting point 128-134 ° C. Mass spectrum 448 (M ⁺¹ ). ¹ H-NMR (DMSO-d _6, 400 MHz) δ 10.66 (1H, br s), 7.79 (1H, s), 7.76 (2H, d), 7.66 (1H, d), 7.61 (2H, d) , 7.34 (1H, t), 7.15-7.10 (2H, m), 4.14 (2H, m), 3.43 (2H, br s), 3.22 (2H, m), 3.21-3.00 (6H, m), 2.78 ( 3H, s).

Example 10 2- [2- (4-Methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one

Sodium hydride (930 mg, 23.3 mmol of 60% oil dispersion) under nitrogen atmosphere was washed with hexane and suspended in 100 mL of dry THF. To this, thiomorpholin-3-one (1.0 g, 8.55 mmol) was added, followed immediately by 2- (4-methylpiperazin-1-yl) -benzaldehyde (1.58 g, 7.75 mmol). The reaction was then heated to reflux overnight, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with aqueous ammonium chloride (NH ₄ Cl) and saturated brine and then dried over MgSO ₄ . Purification by flash chromatography yielded 2- {hydroxy- [2- (4-methylpiperazin-1-yl) phenyl] -methyl} -thiomorpholin-3-one as a white solid; Melting point 137-139 degreeC, mass spectrum 322 (M ^{+ 1} ).

190 mg (0.6 mmol) of the mixture of this intermediate in 25 mL toluene were treated with 135 mg (0.71 mmol) of p-toluenesulfonic acid and refluxed overnight with a Dean-Stark cooler to obtain azeotropic water. After cooling, the solvent was removed and the residue was dissolved in methylene chloride, washed with saturated aqueous sodium carbonate (Na ₂ CO ₃ ) and saturated brine, dried over magnesium sulfate and concentrated in vacuo to give a brown foam. The free base was crystallized from ethyl acetate / hexanes to give a crystalline solid.

Melting point 133-135 ° C. Mass spectrum 304 (M ⁺¹ ). Elemental analysis for C ₁₆ H ₂₁ N ₃ OS- Calcd: C 63.34, H 6.98, N 13.85. Found: C 63.17, H 7.12, N 13.67.

Except as noted, the following examples were carried out in a similar manner to Example 10:

Example 11: 4- (3,4-dichlorophenyl) -2- [2-fluoro-6- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one

Melting point 146-147 ° C. Mass spectrum 466 (M ⁺¹ ), 468.

Example 12 4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -morpholin-3-one

Melting point 169-171 ° C. (decomposition). Mass spectrum 432 (M ⁺ ), 434, 436.

Example 13: 2- [2,4-Dibromo-6- (4-methylpiperazin-1-yl) -benzylidene] -4- (3,4-dichlorophenyl) -thiomorpholine-3- On

Melting point 166-168 ° C. Mass spectrum 607 (M ⁺¹ ). Elemental Analysis for C ₂₂ H ₂₁ N ₃ OSBr ₂ -Calculated: C 43.59, H 3.49, N 6.93. Found: C 43.56, H 3.25, N 6.89.

Example 14 4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one

Melting point 171-173 ° C. Mass spectrum 448 (M ⁺¹ ).

Conversion to hydrochloride salt and recrystallization from isopropanol with 1.0M HCl in ether gave pale yellow crystals.

Melting point 155-157 ° C. Elemental Analysis for C ₂₂ H ₂₃ N ₃ OSCl ₂ HCl1.5 H ₂ O—calc. C 51.62, H 5.32, N 8.21. Found: C 51.81, H 5.02, N 8.45.

Example 15 4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzyl-thiomorpholin-3-one hydrochloride trihydrate

4- (3,4-dichlorophenyl) -2- [2- (4-methyl-piperazin-1-yl) -benzylidene] -thiomorpholin-3-one in 3 ml of anhydrous methanol (201 mg, 0.5 mmol) was treated with samarium iodide (Aldrich Chemical Co., Milwaukee, WI) in THF and stirred overnight at room temperature under a nitrogen atmosphere. A further 5 ml of Sml ₂ solution was added, and after an additional hour, the solvent was removed in vacuo and the residue was flash chromatographed with ethyl acetate / methanol to elute the free base of the product. Hydrochloride salts were prepared using 1.0 M HCl in ether to give a light tan solid.

Melting point 105-110 ° C. (foam). Elemental Analysis for C ₂₂ H ₂₅ N ₃ OSCl ₂ HCl 3 H ₂ O—calc. C 48.85, H 5.96, N 7.77. Found: C 48.95, H 5.58, N 7.51. ¹ H NMR (CDCl _3, 400 MHz, free base) δ 7.45-7.41 (2H, m), 7.17-7.13 (2H, m), 7.06 (1H, t), 4.16 (1H, m), 4.00-3.86 (2H, m), 3.53 (1H, doublet), 3.10-2.95 (7H, m), 2.61 (4H, br s), 2.37 (3H, s).

Example 16: 4-Methyl-2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one hydrochloride hemihydrate

Under a nitrogen atmosphere, sodium hydride (49 mg, 1.24 mmol, 60% oil dispersion) was washed with hexane and laminated with 6 mL of anhydrous THF. After cooling to 0 ° C., 2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one (250 mg, 0.825 mmol) was added and the reaction stirred for 30 minutes It was. Iodomethane (62 μl, 0.99 mmol) was added to the resulting solution, followed by an additional 10 μl of iodomethane after 15 minutes. After 30 minutes, the solvent was removed in vacuo and the residue dissolved in methylene chloride and washed with aqueous ammonium chloride and aqueous brine. After drying, the solvent was removed in vacuo and the residue was purified by flash chromatography. The free base was converted to the hydrochloride salt as described in Example 15 to prepare the title compound as a pale yellow solid.

Melting point 236-238 ° C. Mass spectrum 318 (M ⁺¹ ). ¹ H NMR (DMSO-d ₆ + D ₂ O 400 MHz) δ7.70 (1H, s), 7.48 (1H, d), 7.30 (1H, t), 7.11-7.04 (2H, m), 3.69 (2H , 3.55-3.30 (2H, br s), 3.29-3.02 (4H, m), 2.97 (3H, s), 2.90 (4H, br s), 2.79 (3H, s). Elemental analysis for C ₁₇ H ₂₃ N ₃ OS · HCl · 0.5 H ₂ O—calculated: C 56.26, H 6.94, N 11.58. Found: C 56.22, H 7.11, N 11.37.

Example 17 4- (3,4-dichlorophenyl) -2- (2-piperazin-1-ylbenzylidene) -thiomorpholin-3-one

Under nitrogen atmosphere, 4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomo in 9 ml of anhydrous 1,2-dichloroethane A mixture of Paulin-3-one (338 mg, 0.756 mmol) was treated with α-chloroethyl chloroformate (98 μl, 0.907 mmol) and refluxed overnight. The solvent was then removed in vacuo and 10 ml of methanol was added and then refluxed for 30 minutes. Following solvent removal, the residue was extracted with methylene chloride and washed with saturated aqueous sodium carbonate (Na ₂ CO ₃ ) and saturated brine, then dried over magnesium sulfate and concentrated to foam. Flash chromatography using triethyl amine / methanol / ethyl acetate (1: 2: 97) gave the purified free base of the title compound.

Melting point 198-200 ° C. Mass spectrum 434 (M ⁺¹ ), 436. Elemental Analysis for C ₂₁ H ₂₁ N ₃ OSCl ₂ -Calculated: C 58.07, H 4.87, N 9.67. Found: C 57.93, H 4.71, N 9.43.

Conversion to hydrochloride salt with 1M HCl in CH ₃ OH and then recrystallization from isopropanol to give a crystalline solid; Melting point 154-155 캜.

Preparation Example 1 2- (4-Methylpiperazin-1-yl) -benzaldehyde

The compound is described in Double Oil. W. Nijhuis et al., Synthesis , 641-645 (1987) or J. J .. J. Watthey et al., Journal of Medicinal Chemistry, 26 , 1116-1122 (1983).

The following analogues were prepared in a similar manner to the preparation of 2- (4-methylpiperazin-1-yl) -benzaldehyde:

4,6-Dibromo-2- (4-methylpiperazin-1-yl) -benzaldehyde

Yield 72%. Melting point 92-93 ° C. Mass spectrum 362. ¹ H NMR (CDCl ₃ , 250 MHz) δ 10.12 (1H, s), 7.44 (1H, d), 7.16 (1H, d), 3.10 (4H, br s), 2.61 (4H, s ), 2.36 (3H, s).

6-fluoro-2- (4-methylpiperazin-1-yl) -benzaldehyde

Yield 69%. Light brown oil. Mass spectrum 223 (M ⁺¹ ). ¹ H NMR (CDCl ₃ , 250 MHz) δ 10.27 (1H, s), 7.45 (1H, m), 7.86 (1H, d), 6.75 (1H, dd), 3.14 (4H, t), 2.62 (4H , t), 2.37 (3H, s).

Preparation Example 2 2,4-Dibromo-6-fluoro-benzaldehyde

In a flame-dried 250 ml round bottom flask equipped with a funnel and a magnetic stir bar, a mixture of diisopropylamine (4.82 ml, 34.66 mmol) in 100 ml of anhydrous THF was cooled to -78 ° C and in THF 2.5N n-butyllithium (13.86 ml, 34.66 mmol) was added dropwise. After stirring for 10 minutes, a mixture of 3,5-dibromo-1-fluorobenzene (8.0 g, 31.51 mmol) in 16 mL THF was added dropwise and stirring continued for an additional 30 minutes. At this point, N, N-dimethylformamide (DMF) (2.68 mL, 34.66 mmol) was added dropwise and stirred at −78 ° C. again for 10 min. The reaction was stopped with saturated aqueous ammonium chloride and the solvent was removed in a rotary evaporator. The residue was dissolved in ether, washed with saturated brine, dried over calcium sulfate, filtered and concentrated to 7.36 g of oil. Purification by flash chromatography using ethyl acetate-hexane (1:99) gave the title compound as a white solid.

Melting point 57-58 ° C. Mass spectrum 281 (M ⁺¹ ), 283. ¹ H NMR (CDCl ₃ , 400 MHz) δ 10.29 (1H, s), 7.66 (1H, t), 7.33 (1H, dd). Elemental Analysis for C ₇ H ₃ Br ₂ FO- Calcd: C 29.82, H 1.07. Found: C 30.25, H 1.03.

Preparation Example 3 3- (4-Chlorobenzyl) -imidazolidine-2,4-dione

In a flame-dried flask under nitrogen atmosphere, 15 ml of potassium salt (1.382 g, 10 mmol) and 4-chlorobenzyl bromide (2.055 g, 10 mmol) of imidazolidine-2,4-dione with magnetic stirring were added. Combined with aqueous N, N-dimethylformamide (DMF) and heated at 170-175 ° C. for 5 hours. The reaction was cooled to room temperature, and then 50 ml of water was added to prepare a white precipitate of beeswax. Recrystallization from ethyl acetate: hexanes gave 0.775 g (34.5%) of the title compound as a white crystalline solid.

Melting point 162-163.5 degreeC (decomposition). ¹ H NMR (DMSO-d ₆ ) δ8.17 (1H, s), 7.34 (4H, q), 4.51 (2H, s), 3.98 (2H, s), 3.35 (HOD, s).

In the same way, the potassium salt of thiazolidine-2,4-dione (1.0 g, 6.45 mmol) is converted to 0.97 g (62%) of 3- (4-chlorobenzyl) -thiazolidine-2,4-dione I was.

¹ H NMR (CDCl ₃ , 250 MHz) δ 7.32 (4H, symbol), 4.73 (2H, 2), 3.95 (2H, s).

Preparation Example 4 4- (3,4-dichlorophenyl) -thiomorpholin-3-one

In a flame-dried flask under a nitrogen atmosphere, sodium hydride (72 mg, 1.79 mmol, 60% oil dispersion) was washed with hexanes, then treated with 6 mL of anhydrous DMF and cooled to 0 ° C. A portion of thiomorpholin-3-one (200 mg, 1.71 mmol) was added while stirring. After stopping evaporation of the gas (about 30 minutes), 4-iodo-1,2-dichlorobenzene (700 mg, 2.56 mmol) was added, followed by copper bromide (I) (490 mg, 3.42 mmol) after 5 minutes. It was. After heating at 75 ° C. overnight, the mixture was separated with ethyl acetate and 1N lithium chloride, then filtered through diatomaceous earth and further mixed with ethyl acetate cleaner of the diatomaceous earth filter cake. The organic layer was further washed with 1N lithium chloride, brine (saturated sodium chloride) and dried over calcium sulfate (CaSO ₄ ). 363 mg of a light brown oil obtained by flash chromatography (ethyl acetate in 30-50% hexanes) was concentrated in vacuo to yield 108 mg of a white solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.44 (1H, d), 7.37 (1H, s), 7.12 (1H, dd), 3.93 (2H, t), 3.43 (2H, s), 3.01 (2H , t).

Preparation Example 5 4- (4-Trifluoromethylphenyl) -thiomorpholin-3-one

A mixture of thiomorpholin-3-one (500 mg, 4.27 mmol), 4-trifluoromethyl-1-iodobenzene (1.25 mL, 8.5 mmol) and copper metal (814 mg, 12.8 mmol) was sealed in a sealed tube. Heated at -200 [deg.] C. for 18 hours. The residue was then purified by flash chromatography to give 260 mg of the title compound as a white solid.

Melting point 85-87 ° C. Mass spectrum 262 (M ⁺¹ ). ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.82 (2H, d), 7.37 (2H, d), 3.97 (2H, t), 3.43 (2H, s), 3.01 (2H, t).

In the same manner, 4- (3,4-dichlorophenyl) -thiomorpholin-3-one was prepared using bronze copper (Aldrich Chemical Corporation, Milwaukee, WI) and 170 ° C. in a round bottom flask under nitrogen atmosphere. Isolated at a yield of 37-46%; Melting point 79 to 80 ° C.

Preparation Example 6 4-benzylthiomorpholin-3-one

In a flame-dried flask under a nitrogen atmosphere, sodium hydride (4.65 g, 0.105 mol, 54% oil dispersion) was added to 150 mL of anhydrous dimethylformamide (DMF) and the suspension was cooled to 0 ° C. While stirring, a portion of thiomorpholin-3-one (11.7 g, 0.1 mol) was added over 30 minutes. After stopping the gas evaporation (about 30 minutes), benzyl chloride (12.1 g, 0.105 mol) in DMF (50 mL) was added and stirring continued at room temperature overnight. The reaction was then heated to 80 ° C. for 15 minutes and then cooled. Water (250 mL) was added and the mixture was extracted with dried (with MgSO ₄ ) chloroform and then concentrated in vacuo to an oil. The oil was triturated with ethyl ether (Et ₂ O) and cooled with dry ice to give 12.75 g of a solid product; Melting point 60-62 ° C.

Recrystallization of 5 g from 100 ml of Et ₂ O gave 3.5 g of pure product (melting point 62-63 ° C.) and 0.75 g of second product (melting point 62-63 ° C.)

In the same manner, 4- (3,4-dichlorobenzyl) -thiomorpholin-3-one as a white solid was obtained from 3,4-dichlorobenzyl bromide and thiomorpholin-3-one in a yield of 89%.

Melting point 86-87 ° C. ¹ H NMR (CDCl ₃ , 400 MHz) δ7.38 (1H, d), 7.33 (1H, d), 7.10 (1H, dd), 4.56 (2H, s), 3.55-3.51 (2H, m), 3.37 (2H, s), 2.81-2.76 (2H, m).

Claims (28)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula I Where R ¹ is a group of G ¹ or G ² shown below; a is 0 to 8; R ¹³ are each independently selected from G ¹ of the piperazine ring, or G ² of the piperidine from one of the ring carbons of the ring, the available binding sites of G ¹ of the piperazine ring, or G ² of the piperidine or like Dean ring having (C ₁ -C ₄ ) alkyl to another ring carbon or ring nitrogen or (C ₁ -C ₄ ) methylene bridge, or (C ₁ -C ₄ ) alkyl to ring carbon of R ⁶ with available binding site or (C ₁ -C ₄ ) methylene bridge; X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C ₁ -C ₆ ) alkyl, hydroxy, trifluoromethyl, (C ₁ -C ₆ ) alkoxy, -SO _t (C ₁ -C ₆ ) alkyl, where t is 0, 1 or 2, -CO ₂ R ¹⁰ or -CONR ¹¹ R ¹² ; Y, together with the atom to which it is attached, 1,3-oxazolidin-4-one-5-yl, 1,3-oxazolidin-2,4-dione-5-yl, 4,5-dihydro- 1,2-oxazolidin-3-one-4-yl, 1,3-thiazolidin-4-one-5-yl, 1,3-thiazolidin-2,4-dione-5-yl, 1,3-pyrazolidin-4-one-5-yl, 1,3-imidazolidin-2,4-dione-5-yl, 1,2-pyrazolidin-3-one-4-yl , 1,2-thiazolidine-1,1,3-trion-4-yl, 1,2-thiazolidin-3-on-4-yl, tetrahydro-1,2-oxazine-3- On-4-yl, tetrahydro-1,3-oxazin-4-one-5-yl, tetrahydro-1,3-oxazine-2,4-dione-5-yl, morpholin-3-one -2-yl, morpholine-3,5-dione-2-yl, 2,3-dihydro-1,4-oxazin-3-one-2-yl, tetrahydro-1,3-thiazine- 4-one-5-yl, tetrahydro-1,3-thiazine-2,4-dione-5-yl, tetrahydro-1,2-thiazin-3-one-4-yl, thiomorpholine- 3-on-2-yl, thiomorpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-thiazin-3-one-2-yl, hexahydro-1,2 -Diazin-3-one-4-yl, 4,5-dihydro-2H-pi Dazin-3-one-4-yl, hexahydro-1,3-diazin-4-one-5-yl, hexahydro-1,3-diazine-2,4-dione-5-yl, piperazine -2-one-3-yl, piperazine-2,6-dione-3-yl, tetrahydro-1,3,4-thiadiazine-5-one-6-yl, 5,6-dihydro- 1,3,4-thiadiazine-5-one-6-yl, 1,3,4-oxadiazine-5-one-6-yl, 5,6-dihydro-1,2,4-oxa Diazin-5-one-6yl, tetrahydro-1,2,4-oxadiazine-5-one-6-yl, 1,2,4-triazine-5-one-6-yl, tetrahydro -1,2,4-oxadiazine-5-one-6-yl, 5,6-dihydro-1,2,4-oxadiazine-5-one-6-yl, 1,2,4- Oxadiazine-3,5-dione-6-yl, 1,2,4-trazin-6-one-5-yl, hexahydro-1,2-oxazin-3-one-2-yl, hexa Hydro-1,3-oxazepin-4-one-5-yl, hexahydro-1,4-oxazepin-3-on-2-yl, hexahydro-1,4-oxazepine-3,5-dione -2-yl, hexahydro-1,4-oxazepine-3,5-dione-6-yl, 2,3,5,6-tetrahydro-1,4-oxazepine-5,7-dione-6 -Day, hexahydro-1,4-oxalase -5-one-6-yl, hexahydro-1,3-oxazepine-2,4-dione-5-yl, hexahydro-1,2-thiazepin-3-on-4-yl, hexahydro- 1,4-thiazepin-3-one-2-yl, 2,3,4,5-tetrahydro-1,4-thiazepin-3-one-2-yl, hexahydro-1,4-thiazepine -3,5-dione-2-yl, hexahydro-1,4-thiazepine-3,5-dione-6-yl, 2,3,6,7-tetrahydro-1,4-thiazepine-5 -One-6-yl, 6,7-dihydro-1,4-thiazepin-5-one-6-yl, hexahydro-1,3-thiazepin-2,4-dione-5-yl, hexa Hydro-1,2-diazepin-3-one-4-yl, hexahydro-1,3-diazepin-2,4-dione-5-yl, hexahydro-1,4-diazepin-2-one -3-yl, hexahydro-1,4-diazepin-5-one-6-yl, hexahydro-1,4-diazepin-5,7-dione-6-yl, hexahydro-1,3, 5-thiadiazepin-3-one-7-yl, 4,5,6,7-tetrahydro-1,3,5-thiadiazepin-6-one-7-yl and 2,3,5,6 2-tetrahydro-1,2,4-triazin-3,5-dione-7-yl selected from the group consisting of If the four 5-to 7-membered containing a hetero atom to form a substituted or unsubstituted heterocycle (C ₁ -C ₄₎ heteroalkyl bridge (here, (C ₁ -C ₄₎ of the carbon atoms of the heteroalkyl bridge Substituents on carbon atoms that may have additional bonds are chloro, fluoro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, trifluoromethyl or cyano, and (C ₁ -C ₄ The substituent on the nitrogen atom which may have additional bonds in the nitrogen atom of the heteroalkyl bridge is (C ₁ -C ₆ ) alkyl or trifluoromethyl); R ² is hydrogen, (C ₁ -C ₄ ) alkyl, phenyl or naphthyl, wherein phenyl or naphthyl is unsubstituted or chloro, fluoro, bromo, iodo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) substituted with one or more substituents independently selected from alkoxy, trifluoromethyl, cyano and -SO _k (C ₁ -C ₆ ) alkyl, where k is 0, 1 or 2 Can be; R ³ is — (CH ₂ ) _m B, wherein m is 0, 1, 2 or 3 and B is hydrogen, phenyl, naphthyl or a 5 or 6 membered hetero containing 1 to 4 heteroatoms in the ring Aryl group, wherein each of the phenyl, naphthyl and heteroaryl groups is unsubstituted or chloro, fluoro, bromo, iodo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, ( C ₁ -C ₆ ) alkoxy- (C ₁ -C ₆ ) alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, COOH and SO _n (C ₁ -C ₆ ) alkyl, where n is 0, 1 or 2); R ⁶ is hydrogen; It is optionally substituted with (C ₁ -C ₆₎ alkoxy or one to three fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkyl; Or [(C ₁ -C ₄₎ alkyl] aryl; wherein the aryl moiety is phenyl, naphthyl or heteroaryl - (CH _{2) q} (wherein the heteroaryl moiety is pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl Is selected from the group consisting of zolyl, benzisoxazolyl and benzisothiazolyl, q is 0, 1, 2, 3 or 4), and the aryl and heteroaryl moieties are unsubstituted or substituted with chloro, fluoro, bromo, Iodo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, trifluoromethyl, cyano and SO _g (C ₁ -C ₆ ) alkyl, where g is 0, 1 or 2 May be substituted with one or more substituents independently selected from R ⁸ is hydrogen or (C ₁ -C ₃ ) alkyl; R ¹⁰ , R ¹¹ and R ¹² are each independently selected from radicals as defined in the definition of R ² , or R ¹¹ and R ¹² together with 0 to 4 heteros selected from nitrogen, sulfur and oxygen with the nitrogen to which they are attached To form 5- to 7-membered heteroalkyl rings which may contain atoms; The dashed line indicates a double bond, and the dashed line indicated in G ² is a double bond only when R ⁸ is not present. The method of claim 1, R ¹ is Wherein R ⁶ is methyl and R ² is hydrogen. The method of claim 1, Y, together with the atom to which it is attached, 1,3-thiazolidin-2,4-dione-5-yl, 1,3-imidazolidine-2,4-dione-5-yl, thiomorpholine- A compound that forms an unsubstituted or substituted 5- to 7-membered heterocycle selected from 3-on-2-yl or morpholin-3-on-2-yl. The method of claim 2, Y, together with the atom to which it is bonded, forms a thiomorpholin-3-one-2-yl. The method of claim 1, R ³ is unsubstituted or substituted phenyl or unsubstituted or substituted (CH ₂ ) -phenyl. The method of claim 2, R ³ is unsubstituted or substituted phenyl or unsubstituted or substituted (CH ₂ ) -phenyl. The method of claim 3, wherein R ³ is unsubstituted or substituted phenyl or unsubstituted or substituted (CH ₂ ) -phenyl. The method of claim 4, wherein R ³ is unsubstituted or substituted phenyl or unsubstituted or substituted (CH ₂ ) -phenyl. The method of claim 1, 3- (4-chlorobenzyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -imidazolidine-2,4-dione; 3- (4-Chlorophenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -imidazolidine-2,4-dione; 3- (4-chlorobenzyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidine-2,4-dione; 4-benzyl-2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-dichlorobenzyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 3- (4-Chlorophenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidine-2,4-dione; 3- (4-Trifluoromethylphenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidine-2,4-dione; 2- [2- (4-methylpiperazin-1-yl) -benzylidene] -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one; 2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-Dichlorophenyl) -2- [2-fluoro-6- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -morpholin-3-one; 4- (3,4-Dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-Dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzyl] -thiomorpholin-3-one; 4-methyl-2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2- (2-piperazin-1-ylbenzylidene) -thiomorpholin-3-one; And Pharmaceutically acceptable salts of these compounds Compound selected from the group consisting of. A compound of formula (V) Formula V Where R ¹ is a group of G ¹ or G ² shown below; X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C ₁ -C ₆ ) alkyl, hydroxy, trifluoromethyl, (C ₁ -C ₆ ) alkoxy, -SO _t (C ₁ -C ₆ ) alkyl, where t is 0, 1 or 2, -CO ₂ R ¹⁰ or -CONR ¹¹ R ¹² ; Y, together with the atom to which it is attached, 1,3-oxazolidin-4-one-5-yl, 1,3-oxazolidin-2,4-dione-5-yl, 4,5-dihydro- 1,2-oxazolidin-3-one-4-yl, 1,3-thiazolidin-4-one-5-yl, 1,3-thiazolidin-2,4-dione-5-yl, 1,3-imidazolidin-4-one-5-yl, 1,3-imidazolidin-2,4-dione-5-yl, 1,2-pyrazolidin-3-one-4- 1, 1,2-thiazolidine-1,1,3-trion-4-yl, 1,2-thiazolidin-3-one-4-yl, tetrahydro-1,2-oxazine-3 -On-4-yl, tetrahydro-1,3-oxazine-4-one-5-yl, tetrahydro-1,3-oxazine-2,4-dione-5-yl, morpholin-3- On-2-yl, morpholine-3,5-dion-2-yl, 2,3-dihydro-1,4-oxazin-3-one-2-yl, tetrahydro-1,3-thiazine -4-one-5-yl, tetrahydro-1,3-thiazine-2,4-dione-5-yl, tetrahydro-1,2-thiazin-3-one-4-yl, thiomorpholine -3-one-2-yl, thiomorpholin-3,5-dione-2-yl, 2,3-dihydro-1,4-thiazin-3-one-2-yl, hexahydro-1, 2-diazin-3-one-4-yl, 4,5-dihydro-2H- Ridazin-3-one-4-yl, hexahydro-1,3-diazin-4-one-5-yl, hexahydro-1,3-diazine-2,4-dione-5-yl, pipe Razin-2-one-3-yl, piperazine-2,6-dion-3-yl, tetrahydro-1,3,4-thiadiazine-5-one-6-yl, 5,6-dihydro -1,3,4-thiadiazine-5-one-6-yl, 1,3,4-oxadiazine-5-one-6-yl, 5,6-dihydro-1,2,4- Oxadiazine-5-one-6yl, tetrahydro-1,2,4-oxadiazine-5-one-6-yl, 1,2,4-triazine-5-one-6-yl, tetra Hydro-1,2,4-oxadiazine-5-one-6-yl, 5,6-dihydro-1,2,4-oxadiazine-5-one-6-yl, 1,2,4 Oxadiazine-3,5-dione-6-yl, 1,2,4-trazin-6-one-5-yl, hexahydro-1,2-oxazin-3-one-2-yl, Hexahydro-1,3-oxazepin-4-one-5-yl, hexahydro-1,4-oxazepin-3-one-2-yl, hexahydro-1,4-oxazepine-3,5- Dion-2-yl, hexahydro-1,4-oxazepine-3,5-dione-6-yl, 2,3,5,6-tetrahydro-1,4-oxazepine-5,7-dione- 6-day, hexahydro-1,4-oxa Pin-5-one-6-yl, hexahydro-1,3-oxazepine-2,4-dione-5-yl, hexahydro-1,2-thiazepin-3-on-4-yl, hexahydro -1,4-thiazepin-3-one-2-yl, 2,3,4,5-tetrahydro-1,4-thiazepin-3-one-2-yl, hexahydro-1,4-thia Zepin-3,5-dione-2-yl, hexahydro-1,4-thiazepin-3,5-dione-6-yl, 2,3,6,7-tetrahydro-1,4-thiazepine- 5-one-6-yl, 6,7-dihydro-1,4-thiazepin-5-one-6-yl, hexahydro-1,3-thiazepin-2,4-dione-5-yl, Hexahydro-1,2-diazepin-3-one-4-yl, hexahydro-1,3-diazepine-2,4-dione-5-yl, hexahydro-1,4-diazepin-2- On-3-yl, hexahydro-1,4-diazepin-5-one-6-yl, hexahydro-1,4-diazepine-5,7-dione-6-yl, hexahydro-1,3 , 5-thiadiazepin-2,6-dione-7-yl, 4,5,6,7-tetrahydro-1,3,5-thiadiazepin-6-one-7-yl and 2,3, Line from the group consisting of 5,6-tetrahydro-1,2,4-triazin-3,5-dione-7-yl 2 is optionally substituted to form a 5-to 7-membered heterocycle containing 1 to 4 hetero atom substituted (C ₁ -C ₄₎ heteroalkyl bridge (here, (C ₁ -C ₄₎ heteroalkyl bridge of carbon Substituents on carbon atoms which may have additional bonds in the atom are chloro, fluoro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, trifluoromethyl or cyano, and (C _1- C ₄₎ substituents on the nitrogen atom which may have an additional bond in the nitrogen atom of the heteroalkyl bridge is (C ₁ -C ₆₎ alkyl is methyl or trifluoromethyl), and; R ² is hydrogen, (C ₁ -C ₄ ) alkyl, phenyl or naphthyl, wherein phenyl or naphthyl is unsubstituted or chloro, fluoro, bromo, iodo, (C ₁ -C ₆ ) alkyl, ( C ₁ -C ₆ ) alkoxy, trifluoromethyl, cyano and -SO _k (C ₁ -C ₆ ) alkyl, wherein k is 0, 1 or 2 to be substituted with one or more substituents independently selected from Can; R ³ is — (CH ₂ ) _m B, wherein m is 0, 1, 2 or 3 and B is hydrogen, phenyl, naphthyl or a 5 or 6 membered hetero containing 1 to 4 heteroatoms in the ring Aryl groups, wherein each of the phenyl, naphthyl and heteroaryl groups are unsubstituted or substituted with chloro, fluoro, bromo, iodo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy- (C ₁ -C ₆ ) alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, -COOH and -SO _n (C ₁ -C ₆ ) alkyl, wherein n May be substituted with one or more substituents independently selected from 0, 1 or 2; R ⁶ is hydrogen; It is optionally substituted with (C ₁ -C ₆₎ alkoxy or one to three fluorine atoms, optionally substituted (C ₁ -C ₆₎ alkyl; Or [(C ₁ -C ₄₎ alkyl] aryl; wherein the aryl moiety is phenyl, naphthyl or heteroaryl - (CH _{2) q} (wherein the heteroaryl moiety is pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl Zolyl, benzisoxazolyl and benzisothiazolyl, q is 0, 1, 2, 3 or 4), and the aryl and heteroaryl moieties are unsubstituted or substituted with chloro, fluoro, bromo, Iodo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, trifluoromethyl, cyano and SO _g (C ₁ -C ₆ ) alkyl, where g is 0, 1 or 2 May be substituted with one or more substituents independently selected from R ⁸ is hydrogen or (C ₁ -C ₃ ) alkyl; R ¹⁰ , R ¹¹ and R ¹² are each independently selected from radicals as defined in the definition of R ² , or R ¹¹ and R ¹² together with 0 to 4 heteros selected from nitrogen, sulfur and oxygen with the nitrogen to which they are attached To form 5- to 7-membered heteroalkyl rings which may contain atoms; The dashed line indicates a double bond, and the dashed line indicated in G ² is a double bond only when R ⁸ is not present. The method of claim 10, 4-benzyl-2- {hydroxy- [2- (4-methylpiperazin-1-yl) -phenyl] methyl} -thiomorpholin-3-one; 4- (3,4-dichlorobenzyl) -2- {hydroxy- [2- (4-methylpiperazin-1-yl) -phenyl] methyl} -thiomorpholin-3-one; 2- {hydroxy- [2- (4-methylpiperazin-1-yl) -phenyl] methyl} -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one; 2- {hydroxy- [2- (4-methylpiperazin-1-yl) -phenyl] methyl} -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2-{[2-fluoro-6- (4-methylpiperazin-1-yl) -phenyl] hydroxymethyl} -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2- {hydroxy- [2- (4-methylpiperazin-1-yl) -phenyl] -methyl} -morpholin-3-one; 2-{[2,4-Dibromo-6- (4-methylpiperazin-1-yl) -phenyl] -hydroxymethyl} -4- (3,4-dichlorophenyl) -thiomorpholine-3 -On; 4- (3,4-dichlorophenyl) -2- {hydroxy- [2- (4-methylpiperazin-1-yl) -phenyl] methyl} -thiomorpholin-3-one; 4-benzyl-2- [2- (4-methylpiperazin-1-yl) -benzylidene] -1,1-dioxothiomorpholin-3-one; 4- (3,4-Dichlorophenyl) -2- [3-fluoro-2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-Dichlorophenyl) -2- [5-fluoro-2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -5-trifluoromethylbenzylidene] -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2- {2- [4- (2-methoxyethyl) piperazin-1-yl] -benzylidene} -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2- [2- (4-isopropylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2- [2- (4-ethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (4-Chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 2- [2-Chloro-6- (4-methylpiperazin-1-yl) -benzylidene] -4- (3,4-dichlorophenyl) -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -4-trifluoromethylbenzylidene] -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -1-oxo-thiomorpholin-3-one; 4- (3,4-Dichlorophenyl) -2- (5-fluoro-2-piperazin-1-yl-benzylidene) -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2- [3,6-difluoro-2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-Dichlorophenyl) -2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4-phenyl-2- [2- (3,4,5-trimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 2- [5-fluoro-2- (4-methylpiperazin-1-yl) -benzylidene] -4-phenyl-thiomorpholin-3-one; 4-benzo [1,3] dioxol-5-yl-2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 2- [2- (4-t-butylpiperazin-1-yl) -benzylidene] -4- (3,4-dichlorophenyl) -thiomorpholin-3-one; 3- (3,4-dichlorophenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidin-4-one; 3- [4- (3,4-Dichlorophenyl) -3-oxo-thiomorpholin-2-ylidenemethyl] -6-dimethylamino-2- (4-methylpiperazin-1-yl) -benzonitrile ; 5- [2- (4-methylpiperazin-1-yl) -benzylidene] -2-phenylthiazolidin-4-one; 4- (3,4-dichlorophenyl) -2- [2- (3,4,5-trimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2- [5-methyl-2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 2- [4-Chloro-2- (4-methylpiperazin-1-yl) -benzylidene] -4- (3,4-dichlorophenyl) -thiomorpholin-3-one; 4- (3,4-difluorophenyl) -2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (2,4-difluorophenyl) -2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 2- [4-bromo-2- (4-methylpiperazin-1-yl) -benzylidene] -4- (3,4-dichlorophenyl) -thiomorpholin-3-one; 4- (3,5-Dichlorophenyl) -2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-difluorophenyl) -2- [2- (3,4,5-trimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2- [2- (octahydropyrido [1,2-a] pyrazin-2-yl) -benzylidene] -thiomorpholin-3-one; 2- [2- (4-cyclopropylpiperazin-1-yl) -benzylidene] -4-pyridin-3-yl-thiomorpholin-3-one; 2- [2- (4-cyclopropylpiperazin-1-yl) -benzylidene] -4- (3,4-difluorophenyl) -thiomorpholin-3-one; 2- [2- (4-cyclopropylpiperazin-1-yl) -benzylidene] -4- (3,5-dichlorophenyl) -thiomorpholin-3-one; 4- (3,4-difluorophenyl) -2- [2- (2,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,5-Dichlorophenyl) -2- [2- (2,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-difluorophenyl) -2- [2- (2,4,5-trimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4-benzo [1,3] dioxol-5-yl-2- [2- (4-cyclopropylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -4- (4-fluorophenyl) -thiomorpholin-3-one; 4-benzo [1,3] dioxol-5-yl-2- [2- (2,5-dimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 2- [2- (3,5-dimethylpiperazin-1-yl) -benzylidene] -4-phenylthiomorpholin-3-one; 4- (3,4-Dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; 4- (3,4-dichlorophenyl) -2- [2- (2,4,6-trimethylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; And 2- [2- (4-cyclopropylpiperazin-1-yl) -benzylidene] -4- (3,4-dichlorophenyl) -thiomorpholin-3-one Compound selected from the group consisting of. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete